Novel benzimidazole compounds

ABSTRACT

The present invention is directed to novel benzimidazole derivatives that possess antibacterial activity. The invention also is directed to compositions including the benzimidazole derivatives, and methods for using the same.

FIELD OF INVENTION

[0001] The present invention is directed to novel benzimidazolederivatives that possess antibacterial activity. The invention also isdirected to compositions including the benzimidazole derivatives, andmethods for using the same.

BACKGROUND OF THE INVENTION

[0002] Almost all the major classes of antibiotics have encounteredresistances in clinical applications. The emergence of bacterialresistance to β-lactam antibiotics, macrolides, quinolones, andvancomycin is becoming a major worldwide health problem. The spread ofantibiotic resistance among pathogenic bacteria imposes another seriousproblem for the clinical management of infectious diseases.Particularly, antibiotic resistance among Gram-positive bacteria(staphylococci, enterococci, and streptococci) is becoming increasinglyserious. Entercococci, which are generally resistant to most antibioticsincluding penicillin, cephalosporin and aminoglycosides, used to betreated with either a combination of two antibiotics or vancomycin.However, with the recent increased use of vancomycin inmethicillin-resistance Staphylococcus aureus (MRSA) infections andcolitis due to colstridium fifficile, multiple resistant entercocccusfaecium has been spreading. As such, the last resort for anti-infectivediseases, the Vancomycin family of antibiotics, has now been gravelychallenged in recent years due to the emergence of MRSA strains inclinical practice. There is an urgent need to discover novelantibacterial agents other than analogues of existing antibiotics.

[0003] A considerable amount of attention has focused recently on newRNA-binding molecules for drug discovery. The interactions between RNAand biological macromolecules are clearly essential fore many vitalprocesses in molecular biology. In addition, the excitement overRNA-based viruses has fueled an interest in the development of potentialRNA inhibitors. RNA offers several selective advantages over DNA as atherapeutic agent. First, chromosomal DNA is packaged extensively,significantly limiting its accessibility to small molecule regents.Second, DNA repair systems are available in the cell, whereas analogousenzymes for RNA repair are virtually unknown. Finally, RNA exhibits ahigh level of diversity in terms of tertiary folding, and therefore willlikely have a greater potential for selective targeting based onstructure rather than sequence.

[0004] Historically, however, RNA-based drug discovery has proved to beextremely difficult, and only a few classes of compounds are known tobind RNA with SAR information, for example aminoglycosides and cationicpeptides. Discovery of RNA binders using traditional high throughputassays such as fluorescence, filter binding, SPA, SPR, etc. has provedto be equally unsuccessful.

[0005] Recently, a MS-based high throughput-screening assay has beendeveloped. See, Hofstadler, S. A.; Griffey, R. H. Curr. Opin. DrugDiscovery Dev. 2000, 3, 423-431; Hofstadler, S. A.; Griffey, R. H. Chem.Rev. (Washington, D. C.) 2001, 101, 377-390; Griffey, R. H.; Greig, M.J.; An, H.; Sasmor, H.; Manalili, S. J. Am. Chem. Soc. 1999, 121,474-475; Sannes-Lowery, K. A.; Griffey, R. H.; Hofstadler, S. A. Anal.Biochem. 2000, 280, 264-271; Griffey, R. H.; Sannes-Lowery, K. A.;Drader, J. J.; Mohan, V.; Swayze, E. E.; Hofstadler, S. A. J. Am. Chem.Soc. 2000, 122, 9933-9938, and Griffey, R. H.; Hofstadler, S. A.;Sannes-Lowery, K. A.; Ecker, D. J.; Crooke, S. T. Proc. Natl. Acad. Sci.U.S.A. 1999, 96, 10129-10133, each of which is incorporated herein byreference in its entirety.

[0006] This assay is extremely sensitive and could detect RNA binderswith Kd values ranging from nanomolar to minimolar. Coupled with massassays to carry out competition experiments and determine the bindinglocations, such assays can be used to discover of novel compounds thatbind to bacterial ribosomal RNA.

[0007] In view of the great importance of antibacterial compounds inanimal, and particularly human health, it can be seen that there is aneed for novel antibacterial agents. The present invention is thereforedirected to, inter alia, such compounds and their uses, as well as otherimportant ends.

SUMMARY OF THE INVENTION

[0008] The present invention also provides compositions containing thesubject compounds, and methods for using the subject compounds.Methodologies for making the compounds of the invention are alsodisclosed. Other useful methodologies will be apparent to those skilledin the art, once armed with the present disclosure. These and otherfeatures of the compounds of the subject invention are set forth in moredetail below.

[0009] In some embodiments, compounds are provided having the formula:

[0010] wherein:

[0011] R₃ and R₄ are independently each H, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, or NO₂;

[0012] R₃₀ is C₁₋₆ alkyl, heteroarylalkyl, arylalkyl, or heteroaryl,wherein each of said heteroarylalkyl, arylalkyl, or heteroaryl groupseach can be optionally substituted with up to three substitutentsselected from haloegn, NO₂, and mono-, di-, or trihaloalkyl;

[0013] or R₃₀ has the structure XX:

[0014] wherein R₃₁ is alkylamino, aminoalkylamino,poly(alkylamino)amino, heterocycloalkylamino, heterocycloalkyl,—NH—(CHOH)₄—CH₂OH, —NH—(CH₂)₁₋₁₂-heteroaryl or—NH—(CH₂)₁₋₁₂-heterocycloalkyl.

[0015] In a further aspect, the present invention provides dimericbenzimidazole compounds having the structure:

[0016] wherein:

[0017] R₂ is NH₂ or piperidin-4-yl;

[0018] R₅₀ and R₅₁ are each independently selected from H, halogen,C₁-C₆ alkyl, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, and NO₂,wherein said C₁-C₆ alkyl, alkoxycarbonyl, and alkoxy groups can each beoptionally substituted with NR₁₅R₁₆;

[0019] R₁₅ is H, halogen, C₁₋₁₂ alkyl, methylcarbonyl, heterocycloalkyl,arylsulfonyl, heteroarylalkyl, aminoalkyl, arylcarbonyl, branched andstraight chain polyaminoalkyl, or a group of formula CH₂(CHOH)₄CH₂OH,

[0020] wherein said methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, and branched and straightchain polyaminoalkyl groups can be substituted by up to 3 OH groups;

[0021] R₁₆ is H, halogen, or C₁-C₆ alkyl;

[0022] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen; R₆₀ isalkylene having from 1 to 18 carbons, or —R₉—X—R₁₀—)H; R₉ and R₁₀ areeach independently alkylene having from 1 to about 20 carbons; X is—N(R₁₂)—, —C(R₁₃)(R₁₄)— or O; and

[0023] R₁₂, R₁₃ and R₁₄ are each independently H or C₁-C₆ alkyl.

[0024] In a further aspect, the present invention provides compounds offormula:

[0025] wherein:

[0026] R₅₂ and R₅₃ are each independently selected from H, halogen,C₁-C₆ alkyl, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, and NO₂wherein said C₁-C₆ alkyl, alkoxycarbonyl, and alkoxy groups can each beoptionally substituted with NR₁₅R₁₆; R₁₅ is H, halogen, C₁₋₁₂ alkyl,methylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, branched and straight chain polyaminoalkyl, ora group of formula CH₂(CHOH)₄CH₂OH;

[0027] wherein said methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, and branched and straightchain polyaminoalkyl groups can be substituted by up to 3 OH groups;

[0028] R₁₆ is H, halogen, or C₁-C₆ alkyl;

[0029] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen; and z is1 to 6.

[0030] Also privided by the present invention are compounds having theFormula:

[0031] wherein:

[0032] R_(2a) is amino, phenyl, mono- or bicyclic heterocycloalkylhaving 1 or 2 ring nitrogen atoms, mono- or bicyclic heteroaryl having 1or 2 ring nitrogen atoms, cycloalkyl, halogen, heterocycloalkylalkyl(i.e., alkyl sub w′ heterocycloalkyl) having 1 or 2 ring nitrogen atoms,mono- or bicyclic heterocycloalkylamino having 1 or 2 ring nitrogenatoms or a group of formula —S-alkylene-L₁ where L₁ is mono- orbicyclic-heteroaryl having 1 or 2 ring nitrogen atoms;

[0033] wherein each of said amino, phenyl, heterocycloalkyl, heteroaryl,cycloalkyl, heterocycloalkylalkyl, or heterocycloalkylamino groups canbe optionally substituted with a group selected from amino, OH, C₁-C₁₂alkyl, a structure of formula —C(═O)CH(NH₂)—L₂ where L₂ is the sidechain of a naturally occurring alpha amino acid, —C(NH₂)═NH, C₁-C₁₂alkylcarbonyl, mono- or bicyclic heteroaryl having 1 or 2 ring nitrogenatoms, mono- or bicyclic heteroarylalkyl having 1 or 2 ring nitrogenatoms, or S-alkyl-heteroaryl where said heteroaryl is mono- or bicyclichaving 1 or 2 ring nitrogen atoms; and

[0034] R₃ and R₄ are each independently halogen, amino, NO₂, CN, C₁₋₆alkoxy or C₁₋₆ alkyl optionally substituted with up to 3 halogen atoms;and

[0035] R₃₀ is H, alkyl, aryl, arylalkyl, heteroaryl; heteroarylalkyl,heterocycloalkyl, arylsulfonyl, aryloxycarbonyl, alkoxyalkoxyalkyl,alkyl-S—R₇, alkyl-NH—C(═O)—R₈ or —R₉—X—R₁₀—R₁₁)H;

[0036] wherein each of the alkyl, aryl, arylalkyl heteroaryl,heteroarylalkyl, heterocycloalkyl, arylsulfonyl, aryloxycarbonyl andalkoxyalkoxyalkyl moieties in each of the foregoing R₁ groups can beoptionally substituted with up to 3 groups independently selected fromthe group consisting of C₁-C₆ alkyl, OH, hydroxyalkyl, —C(═O)—R₅; CN,aryl, alkoxycarbonyl, alkylaryl, arylalkyl, heteroaryl, S-heteroaryloptionally substituted with halogen, heteroarylalkyl optionallysubstituted with halogen, heterocycloalkyl optionaly substituted withamino, NO₂, halogen, monohaloalkyl, dihaloalkyl, trihaloalkyl,perhaloaryl, perhaloalkylaryl, alkyl-NR₁₅R₁₆ and NR₁₅R₁₆;

[0037] or one of said alkyl, aryl, arylalkyl heteroaryl,heteroarylalkyl, heterocycloalkyl, arylsulfonyl, aryloxycarbonyl oralkoxyalkoxyalkyl moieties of one of said R₁ groups can be attached to astructure of Formula I at position R₁ thereof;

[0038] R₅ is H, —NHNHR₆, —NHN═CH—R₆, heteroaryl, heterocycloalkyl,wherein said hereteroaryl group can be optionally substituted with anaryl or heteroaryl group,

[0039] R₆ is aryl, heteroaryl; arylsulfonyl, heteroarylsulfonyl,—C(═S)—NH-aryl, —C(═S)—NH-arylcarbonyl —C(═S)—NH-heteroarylcarbonyl,—C(═S)—NH-alkylene-R₂₁, —C(═O)—NH-aryl, —C(═O)—NH-arylcarbonyl,—C(═O)—NH-heteroarylcarbonyl, or —C(═O)—NH-alkylene-R₂₁ where R₂₁ iscarboxy, alkoxycarbonyl, aryl, heteroaryl, heterocycloalkyl,arylaminocarbonyl, cycloalkylaminocarbonyl, or a saturated hydrocarbonfused ring system optionally having an aryl ring fused thereto, saidring system being optionally substituted with up to three alkyl groupson the alkyl or aryl rings thereof;

[0040] wherein any of said R₆ groups can be optionally substituted withup to 3 groups selected from NR₁₅R₁₆, alkyl, hydroxy, halogen, aryl,alkoxy, trihaloalkoxy, arylalkyloxy, NO₂, —SH, —S-alkyl,heteroarylcarbonyl, heteroaryl, alkylheteroaryl, or a moiety of formula—OC₂CH₂—O— attached to adjacent atoms of said R₆ group;

[0041] R₇ is heteroaryl or heterocycloalkyl;

[0042] R₈ is aryl;

[0043] R₉ and R₁₀ are each independently alkylene having from 1 to about20 carbons;

[0044] X is —N(R₁₂)—, —C(R₁₃)(R₁₄)— or O;

[0045] R₁₁ is H, heterocycloaryl or alkoxy, wherein said heterocycloarylor alkoxy group can be optionally substituted with up to four groupsindependently selected from halogen, amino, trihaloalkyl,alkoxycarbonyl, and CN;

[0046] R₁₂ is H or C₁-C₆ alkyl; and

[0047] R₁₃ and R₁₄ are each independently H or C₁-C₆ alkyl;

[0048] R₁₅ is H, halogen, C₁₋₁₂ alkyl, methylcarbonyl, heterocycloalkyl,arylsulfonyl, heteroarylalkyl, aminoalkyl, arylcarbonyl, branched andstraight chain polyaminoalkyl, or a group of formula CH₂(CHOH)₄CH₂OH,

[0049] wherein said methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, and branched and straightchain polyaminoalkyl groups can be substituted by up to 3 OH groups;

[0050] R₁₆ is H, halogen, or C₁-C₆ alkyl;

[0051] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen, or agroup of Formula I at position R₁ threreof;

[0052] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a group of Formula I wherein said nitrogen atom is Q₄thereof;

[0053] Also provided by the present invention are compounds of Formula:

[0054] wherein:

[0055] Q₅ is CH or N;

[0056] Q₆ is C—R₆₁ or N;

[0057] Q₇ is C—R₆₀ or N;

[0058] R₆₀ and R₆₁ are each independently H, halogen, C₁₋₆ alkyl,trihaloalkyl, or C₁₋₆ alkoxy;

[0059] provided that when Q₆ is C—R₆₁, Q₇ is C—R₆₀ and Q₅ is CH, thenR₆₀ and R₆₁ are not both H.

[0060] The present invention provides methods for treating a patienthaving a bacterial infection comprising administering to said patient acompound of the invention. Preferably, said patient is a human. Alsoprovided are methods for inhibiting bacterial growth comprisingcontacting a bacterium with a compound of the invention. In somepreferred embodiments, said bacterium a gram-positive bacteria,preferably from among staphylococci, enterococci, and streptococci. Insome embodiments the bacterium is S. aureus, E. hirae, S. pyogenes, S.pneumoniae, E. coli, P. vulgaris, K. pneumoniae, P. aeruginosa, C.albicans, E. faecalis, E. faecali, or E. faecium.

[0061] The present invention also provides compositions that include atleast one compound of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0062]FIG. 1 is a table showing activity of benzimidazoles of Examples11 and 12 against four strains of Gram positive and four strains of gramnegative bacteria.

[0063]FIG. 2 is a table showing activity of benzimidazoles of Examples11 and 12 against seven clinically important strains of entercocccus.

[0064]FIG. 3 shows the in vitro inhibitorial activity of selectedbenzimidazoles of Example 16 against four Gram positive bacterialstrains, four gram negative bacterial strains and one yeast strain.

DETAILED DESCRIPTION

[0065] The present invention also provides compositions containing thesubject compounds, and methods for using the subject compounds.Methodologies for making the compounds of the invention are alsodisclosed. Other useful methodologies will be apparent to those skilledin the art, once armed with the present disclosure. These and otherfeatures of the compounds of the subject invention are set forth in moredetail below.

[0066] In some embodiments, compounds are provided having the formula:

[0067] wherein:

[0068] R₃ and R₄ are independently each H, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, or NO₂;

[0069] R₃₀ is C₁₋₆ alkyl, heteroarylalkyl, arylalkyl, or heteroaryl,wherein each of said heteroarylalkyl, arylalkyl, or heteroaryl groupseach can be optionally substituted with up to three substitutentsselected from haloegn, NO₂, and mono-, di-, or trihaloalkyl;

[0070] or R₃₀ has the structure XX:

[0071] wherein R₃₁ is alkylamino, aminoalkylamino,poly(alkylamino)amino, heterocycloalkylamino, heterocycloalkyl,—NH—(CHOH)₄—CH₂OH, —NH—(CH₂)₁₋₁₂-heteroaryl or—NH—(CH₂)₁₋₁₂-heterocycloalkyl.

[0072] In some embodiments, R₃₀ has the structure XX. In some suchembodiments, R₃₁ has the structure of any of the radicals shown inExample 11, designated for compounds 7a-x, infra.

[0073] In further embodiments, R₁ is pyridin-4-yl-methyl,pyridin-3yl-methyl, 4-fluorophen-1-yl-methyl, 4-nitrophen-1-yl-methyl,4-(bromomethyl)phen-1-yl-methyl, pyrimidine-2-yl, or2,4-dinitrophen-1-yl.

[0074] In a further aspect, the present invention provides dimericbenzimidazole compounds having the structure:

[0075] wherein:

[0076] R₂ is NH₂ or piperidin-4-yl;

[0077] R₅₀ and R₅₁ are each independently selected from H, halogen,C₁-C₆ alkyl, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, and NO₂,wherein said C₁-C₆ alkyl, alkoxycarbonyl, and alkoxy groups can each beoptionally substituted with NR₁₅R₁₆; R₁₅ is H, halogen, C₁₋₁₂ alkyl,methylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, branched and straight chain polyaminoalkyl, ora group of formula CH₂(CHOH)₄CH₂OH,

[0078] wherein said methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, and branched and straightchain polyaminoalkyl groups can be substituted by up to 3 OH groups;

[0079] R₁₆ is H, halogen, or C₁-C₆ alkyl;

[0080] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen;

[0081] R₆₀ is alkylene having from 1 to 18 carbons, or —R₉—X—R₁₀—)H;

[0082] R₉ and R₁₀ are each independently alkylene having from 1 to about20 carbons;

[0083] X is —N(R₁₂)—, —C(R₁₃)(R₁₄)— or O; and

[0084] R₁₂, R₁₃ and R₁₄ are each independently H or C₁-C₆ alkyl.

[0085] In some embodiments if the dimeric compounds, R₂ ispiperidin-4-yl. In further embodiments, R₅₀ and R₅₁ are each halogen,preferably chlorine.

[0086] In some embodiments, R₆₀ is alkylene having from 1 to 6 carbonsor from 1 to 4 carbons. In some embodiments, R₆₀ is —CH₂—C₆H₄—CH₂—,preferably where —CH₂—C₆H₄—CH₂— is a para-α,α-xylene radical.

[0087] In some of the foregoing embodiments, R₂ is NH₂. I furtherembodiments, R₅₀ and R₅₁ are each independently selected from H,halogen, methyl, COOCH₃, CN and CF₃.

[0088] In some embodiments, R₆₀ is —R₉—X—R₁₀—. In further embodiments, Xis —N(R₁₂)—. In some embodiments, R₁₂ is methyl and R₉ and R₁₀ are each(CH₂)₂ or (CH₂)₃, preferably wherein R₅₀ and R₅₁ are each halogen, orwhere R₅₀ and R₅₁ are each H, or where R₅₀ is Br and R₅₁ is H, or whereR₅₀ is CH₃ and R₅₁ is H, or where COOCH₃ and R₅₁ is H, or where CF₃ andR₅₁ is H, or where R₅₀ is CN and R₅₁ is H.

[0089] In some embodiments, X is O. I some such embodiments, R₉ and R₁₀are each (CH₂)₂ or (CH₂)₃, preferably where R₅₀ and R₅₁ are eachhalogen, or where R₅₀ and R₅₁ are each H, or where Br and R₅₁ is H, orwhere R₅₀ is CH₃ and R₅₁ is H, or where R₅₀ is COOCH₃ and R₅₁ is H, orwhere R₅₀ is CF₃ and R₅₁ is H, or where R₅₀ is CN and R₅₁ is H.

[0090] In a further aspect, the present invention provides compounds offormula:

[0091] wherein:

[0092] R₅₂ and R₅₃ are each independently selected from H, halogen,C₁-C₆ alkyl, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, and NO₂,wherein said C₁-C₆ alkyl, alkoxycarbonyl, and alkoxy groups can each beoptionally substituted with NR₁₅R₁₆; R₁₅ is H, halogen, C₁₋₁₂ alkyl,methylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, branched and straight chain polyaminoalkyl, ora group of formula CH₂(CHOH)₄CH₂OH;

[0093] wherein said methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, and branched and straightchain polyaminoalkyl groups can be substituted by up to 3 OH groups;

[0094] R₁₆ is H, halogen, or C₁-C₆ alkyl;

[0095] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen; and z is1 to6.

[0096] In some embodiments, R₁₅ and R₁₆ are each methyl, preferablywherein z is 2 or 3, further preferably where R₅₂ and R₅₃ are eachindependently H, C₁₋₆ alkyl, alkoxy optionally substituted withdialkylamino, or alkylamino. In further embodiments, R₅₂ is H,preferably where R₅₃ is methyl, methoxy, alkoxy optionally substitutedwith dialkylamino, or alkylamino, preferably wherein R₅₃ is OCH₃ orO(CH₂)₃N(CH₃)₂.

[0097] In some embodiments, where R₁₅ and R₁₆ are each methyl, z is 2 or3 and R₅₂ is H, C₁₋₆ alkyl, alkoxy optionally substituted withdialkylamino, or alkylamino, R₅₃ is H. In some such embodiments, R₅₂ ismethyl, methoxy, alkoxy optionally substituted with dialkylamino, oralkylamino. In further embodiments, R₅₂ is OCH₃ or O(CH₂)₃N(CH₃)₂.

[0098] Also privided by the present invention are compounds having theFormula:

[0099] wherein:

[0100] R_(2a) is amino, phenyl, mono- or bicyclic heterocycloalkylhaving 1 or 2 ring nitrogen atoms, mono- or bicyclic heteroaryl having 1or 2 ring nitrogen atoms, cycloalkyl, halogen, heterocycloalkylalkyl(i.e., alkyl sub w′ heterocycloalkyl) having 1 or 2 ring nitrogen atoms,mono- or bicyclic heterocycloalkylamino having 1 or 2 ring nitrogenatoms or a group of formula —S-alkylene-L₁ where L₁ is mono- orbicyclic-heteroaryl having 1 or 2 ring nitrogen atoms;

[0101] wherein each of said amino, phenyl, heterocycloalkyl, heteroaryl,cycloalkyl, heterocycloalkylalkyl, or heterocycloalkylamino groups canbe optionally substituted with a group selected from amino, OH, C₁-C₁₂alkyl, a structure of formula —C(═O)CH(NH₂)—L₂ where L₂ is the sidechain of a naturally occurring alpha amino acid, —C(NH₂)═NH, C₁-C₁₂alkylcarbonyl, mono- or bicyclic heteroaryl having 1 or 2 ring nitrogenatoms, mono- or bicyclic heteroarylalkyl having 1 or 2 ring nitrogenatoms, or S-alkyl-heteroaryl where said heteroaryl is mono- or bicyclichaving 1 or 2 ring nitrogen atoms; and

[0102] R₃ and R₄ are each independently halogen, amino, NO₂, CN, C₁₋₆alkoxy or C₁₋₆ alkyl optionally substituted with up to 3 halogen atoms;and

[0103] R₃₀ is H, alkyl, aryl, arylalkyl, heteroaryl; heteroarylalkyl,heterocycloalkyl, arylsulfonyl, aryloxycarbonyl, alkoxyalkoxyalkyl,alkyl-S—R₇, alkyl-NH—C(═O)—R₈ or —R₉—X—R₁₀—R₁₁)H;

[0104] wherein each of the alkyl, aryl, arylalkyl heteroaryl,heteroarylalkyl, heterocycloalkyl, arylsulfonyl, aryloxycarbonyl andalkoxyalkoxyalkyl moieties in each of the foregoing R₁ groups can beoptionally substituted with up to 3 groups independently selected fromthe group consisting of C₁-C₆ alkyl, OH, hydroxyalkyl, —C(═O)—R₅, CN,aryl, alkoxycarbonyl, alkylaryl, arylalkyl, heteroaryl, S-heteroaryloptionally substituted with halogen, heteroarylalkyl optionallysubstituted with halogen, heterocycloalkyl optionaly substituted withamino, NO₂, halogen, monohaloalkyl, dihaloalkyl, trihaloalkyl,perhaloaryl, perhaloalkylaryl, alkyl-NR₁₅R₁₆ and NR₁₅R₁₆;

[0105] or one of said alkyl, aryl, arylalkyl heteroaryl,heteroarylalkyl, heterocycloalkyl, arylsulfonyl, aryloxycarbonyl oralkoxyalkoxyalkyl moieties of one of said R₁ groups can be attached to astructure of Formula I at position R₁ thereof;

[0106] R₅ is H, —NHNHR₆, —NHN═CH—R₆, heteroaryl, heterocycloalkyl,wherein said hereteroaryl group can be optionally substituted with anaryl or heteroaryl group,

[0107] R₆ is aryl, heteroaryl; arylsulfonyl, heteroarylsulfonyl,—C(═S)—NH-aryl, —C(═S)—NH-arylcarbonyl, —C(═S)—NH-heteroarylcarbonyl,—C(═S)—NH-alkylene-R₂₁, —C(═O)—NH-aryl, —C(═O)—NH-arylcarbonyl,—C(═O)—NH-heteroarylcarbonyl, or —C(═O)—NH-alkylene-R₂₁ where R₂₁ iscarboxy, alkoxycarbonyl, aryl, heteroaryl, heterocycloalkyl,arylaminocarbonyl, cycloalkylaminocarbonyl, or a saturated hydrocarbonfused ring system optionally having an aryl ring fused thereto, saidring system being optionally substituted with up to three alkyl groupson the alkyl or aryl rings thereof;

[0108] wherein any of said R₆ groups can be optionally substituted withup to 3 groups selected from NR₁₅R₁₆, alkyl, hydroxy, halogen, aryl,alkoxy, trihaloalkoxy, arylalkyloxy, NO₂, —SH, —S-alkyl,heteroarylcarbonyl, heteroaryl, alkylheteroaryl, or a moiety of formula—OC₂CH₂—O— attached to adjacent atoms of said R₆ group;

[0109] R₇ is heteroaryl or heterocycloalkyl;

[0110] R₈ is aryl;

[0111] R₉ and R₁₀ are each independently alkylene having from 1 to about20 carbons;

[0112] X is —N(R₁₂)—, —C(R₁₃)(R₁₄)— or O;

[0113] R₁₁ is H, heterocycloaryl or alkoxy, wherein said heterocycloarylor alkoxy group can be optionally substituted with up to four groupsindependently selected from halogen, amino, trihaloalkyl,alkoxycarbonyl, and CN;

[0114] R₁₂ is H or C₁-C₆ alkyl; and

[0115] R₁₃ and R₁₄ are each independently H or C₁-C₆ alkyl;

[0116] R₁₅ is H, halogen, C₁₋₁₂ alkyl, methylcarbonyl, heterocycloalkyl,arylsulfonyl, heteroarylalkyl, aminoalkyl, arylcarbonyl, branched andstraight chain polyaminoalkyl, or a group of formula CH₂(CHOH)₄CH₂OH,

[0117] wherein said methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, and branched and straightchain polyaminoalkyl groups can be substituted by up to 3 OH groups;

[0118] R₁₆ is H, halogen, or C₁-C₆ alkyl;

[0119] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen, or agroup of Formula I at position R₁ threreof;

[0120] or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a group of Formula I wherein said nitrogen atom is Q₄thereof;

[0121] In some such embodiments, R₃ and R₄ are each halogen, preferablychlorine. In further embodiments, R_(2a) is amino, Cl, phenyl,monocyclic heterocycloalkyl having 1 or 2 ring nitrogen atoms,monocyclic heteroaryl having 1 ring nitrogen atom, cyclopenyl,cyclohexyl, heterocycloalkyl-methyl, piperidine-4-yl amino or a group offormula —S—(C₂₋₄ alkylene)-N-phthalimido; wherein each of said phenyl,heterocycloalkyl heteroaryl, cyclopenyl, cyclohexyl,heterocycloalkyl-methyl, and piperidine-4-yl amino groups can beoptionally substituted with a group selected from NH₂, OH, CH₃, COOCH₃,a structure of formula —C(═O)CH(NH₂)—L₂ where L2 is a serine orthreonine side chain, —C(NH₂)═NH, benzimidazolyl, orbenzimidazolemethylyl.

[0122] In further embodiments, R_(2a) is amino, Cl, piperidinyl,pyridinyl, phenyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,—CH₂-piperazinyl, piperidine-4-yl-amino or S-alkyl-phthalyl, whereinsaid piperidinyl, pyridinyl, phenyl, cyclopentyl, cyclohexyl,pyrrolidinyl, piperazinyl, —CH₂-piperazinyl, or S-alkyl-phthalyl groupscan be optionally substituted with a group selected from NH₂,methylcarbonyl, —C(═O)CH(NH₂)—CH₂OH, methyl, OH, —C(NH₂)═NH, OH,benzimidazole-2-yl, and —CH₂-benzimidazole-2-yl.

[0123] In still further embodiments, R_(2a) is amino, Cl, piperidinyl,pyridinyl, phenyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,—CH₂-piperazinyl, piperidine-4-yl-amino or S-alkyl-phthalyl, whereinsaid piperidinyl, pyridinyl, phenyl, cyclopentyl, cyclohexyl,pyrrolidinyl, piperazinyl, —CH₂-piperazinyl, or S-alkyl-phthalyl groupscan be optionally substituted with a group selected from NH₂,methylcarbonyl, —C(═O)CH(NH₂)—CH₂OH, methyl, OH, —C(NH₂)═NH, OH,benzimidazole-2-yl, and —CH₂-benzimidazole-2-yl.

[0124] In further embodiments, R_(2a) is amino, Cl, pyridin-4-yl, phenylsubstituted with amino, cyclopentyl substituted with amino, cyclohexyloptionally substituted with amino, pyrrolidin-2-yl optionallysubstituted by hydroxy, piperazin-1-yl optionally substituted at the4-yl position by benzimidazole-2-yl, piperazin-1-yl-methyl optionallysubstituted at the 4-yl position by —CH₂-benzimidazole-2-yl,piperidine-4-yl-amino, piperidin-1-yl substituted by amino,S-alkyl-phthalyl, or said R₂ is piperidin-4-yl optionally substituted atthe 1-yl position with —C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH, —C(NH₂)═NH, orCH₃.

[0125] In still further embodiments, R_(2a) is amino,piperidin-4-yl-amino, piperiazine-1-yl optionally substituted withbenzimidazole-2-yl, pyridin-4-yl, piperidin-4-yl optionally substitutedat the 1-yl position with —C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH, —C(NH₂)═NH, orCH₃, 4-amino-piperdin-1-yl, 3-amino-phen-1-yl, 3-amino-cyclopent-1-yl,cyclohexyl optionally substituted at the 3-yl or 4-yl position with NH₂,4-hydroxypyrrolidin-2-yl, piperazin-1-yl-methyl,4-(benzimidazole-2-yl-methyl)piperazin-1-yl-methyl, or S-alkyl-phthalylwhere said alkyl has from 2 to 4 carbons.

[0126] In still further embodiments, R_(2a) is piperidin-4-yl optionallysubstituted at the 1-yl position with —C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH,—C(NH₂)═NH, or CH₃.

[0127] In further embodiments where R₃ and R₄ are each chlorine, R_(2a)is piperidin-4-yl optionally substituted at the 1-yl position with—C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH, —(NH₂)═NH, or CH₃.

[0128] In some embodiments, R_(2a) is piperidin-4-yl, and, preferably R₃and R₄ are each chlorine. In some embodiments, R_(2a) is NH₂, preferablywherein R₃ and R₄ are each chlorine.

[0129] In some embodiments where R₃ and R₄ are each chlorine and R_(2a)is piperidin-4-yl, R₃₀ is alkyl substituted with —C(═O)—R₅, preferablywherein R₅ is —NHNHR₆, or —NHN═CH—R₆.

[0130] In some such embodiments, R₅ is —NHNHR₆ where R₆ is—C(═O)—NH-aryl, —C(═O)—NH-cycloalkyl, —C(═S)—NH-aryl, arylsulfonyl,heteroarylsulfonyl, heterocycloalkyl, arylaminocarbonyl,cycloalkylaminocarbonyl, —C(═S)—NH-alkylene-R₂₁ where R₂₁ is heteroarylor heterocycloaryl, or a saturated hydrocarbon fused ring systemoptionally having an aryl ring fused thereto, said ring system beingoptionally substituted with up to three alkyl groups on the alkyl oraryl rings thereof; wherein any of said R₆ groups can be optionallysubstituted with up to 3 groups selected from NR₁₅R₁₆, NO₂, a moiety offonrula —OC₂CH₂—O— attached to adjacent atoms of said R₆ group, aryl,C₁₋₆ alkoxy, carboxy, or C₁₋₆ trihaloalkoxy.

[0131] In some embodiments, R₅ is —NHN═CH—R₆. In some such embodiments,R₆ is aryl or heteroaryl optionally substituted with up to 3 groupsselected from OH, C₁₋₆ alkoxy, NO₂, C₁₋₆ trihaloalkoxy, C₁₋₆trihaloalkyl, aryl, arylalkyloxy, and a moiety of formula —OC₂CH₂—O—attached to adjacent atoms of said R₆ group.

[0132] In some embodiments wherein R_(2a) is piperidin-4-yl, R₃₀ has theformula —(CH₂)_(q)—L₄ where q is 0 to 6 and L₄ is aryl, heteroaryl orheterocycloalkyl, arylsulfonamino, arylcarboxyamino or —S-heteroaryl,where each of said L₄ is optionally substituted with up to threesubstituents selected from halogen and NO₂. Preferably, said L₄ ismaleimido, succinimido, phthalimido, naphthalimido, pyromelliticdiimido, phenylsulfonamido, phenylcarboxamido, benzopyrrolidine,benzimidazole, triazole, or —S-benzimidazole.

[0133] Also provided by the present invention are compounds of Formula:

[0134] wherein:

[0135] Q₅is CH or N;

[0136] Q₆ is C—R₆₁ or N;

[0137] Q₇ is C—R₆₀ or N;

[0138] R₆₀ and R₆₁ are each independently H, halogen, C₁₋₆ alkyl,trihaloalkyl, or C₁₋₆ alkoxy; provided that when Q₆ is C—R₆₁, Q₇ isC—R₆₀ and Q₅is CH, then R₆₀ and R₆₁ are not both H.

[0139] In some embodiments, Q₅ is N. In further embodiments, Q₆ is N.

[0140] In some embodiments, Q₇ is N. In further embodiments, Q₅ is N, Q₆is C—R₆₁ and Q₇ is C—R₆₀. In further embodiments, Q₇ is N, Q₆ is C—R₆₁and Q₅ is CH. In further embodiments, Q₅ is N, Q₆ is N and Q₇ is C—R₆₀.In further embodiments, Q₅ is CH, Q₆ is R₆₁ and Q₇ is C—R₆₀.

[0141] In some embodiments where Q₅ is CH, Q₆ is R₆₁ and Q₇ is C—R₆₀,R₆₀ and R₆₁ are each independently H, Br, Cl, methoxy, methyl ortrifluoromethyl. In further such embodiments, R₆₀ is OCH₃ and R₆₁ is H,or R₆₀ is CH₃ and R₆₁ is H, or R₆₀ is Br and R₆₁ is H, or R₆₀ is Cl andR₆₁ is H, or R₆₀ is CF₃ and R₆₁ is H, or R₆₀ is Cl and R₆₁ is CH₃, R₆₀and R₆₁ are both Cl.

[0142] The present invention provides methods for treating a patienthaving a bacterial infection comprising administering to said patient acompound of claim 1. Preferably, said patient is a human. Also providedare methods for inhibiting bacterial growth comprising contacting abacterium with a compound of the invention. In some preferredembodiments, said bacterium is S. aureus, E. hirae, S. pyogenes, S.pneumoniae, E. coli, P. vulgaris, K. pneumoniae, P. aeruginosa, C.albicans, E. faecalis, E. faecali, or E. faecium.

[0143] The present invention also provides compositions that include atleast one compound of the invention.

[0144] As used herein the term alkyl is intended to have it accustomedmeaning of a straight or branched chain hydrocarbon, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl,n-pentyl, sec-pentyl, t-pentyl, neopentyl, and the like.

[0145] As used herein the term aryl is intended to mean an aromatichydrocarbon system for example phenyl, naphthyl, phenanthrenyl,anthracenyl, pyrenyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms.

[0146] As used herein, the term arylalkyl (or “aralkyl”) is intended tomean an alkyl group that has an aryl group appended thereto, for examplebenzyl and naphthylmethyl groups. In some embodiments, arylalkyl groupshave from 7 to 11 carbon atoms.

[0147] As used herein, the term alkylaryl (or “alkaryl”) is intended tomean an aryl group that has one or more alkyl groups appended thereto,for example a 4-methylphen-1-yl group, or a xylyl group attached throughthe phenyl ring thereof.

[0148] As used herein, the term heteroaryl means an aryl group thatcontains one or more ring hetero (i.e., non-carbon) atoms, which arepreferably O, N or S, more preferably N. In some embodiments, heteroarylgroups are monocyclic or bicyclic, and have up to four ring nitrogenatoms. Examples of some preferred heteroaryl groups include radicalsderived from pyrrole, pyrazole, imidazole, triazoles, tetrazole,pyridine, pyrazine, pyridazine, pyrimidine, triazines, quinolines,indoles, benzimidazoles, and the like.

[0149] As used herein, the term heteroarylalkyl is intended to mean analkylene group that has a heteroaryl group appended thereto, for examplea group of formula —CH₂-benzimidazol-2-yl.

[0150] As used herein, the term cycloalkyl refers to nonaromatichydrocarbon ring systems, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, including multiple ring systems such asdecahydronaphthalene and adamantane. Cycloalkyl groups can also includepoints of unsaturation, and therefor also include cyclopentenyl, andcyclohexenyl groups.

[0151] As used herein, the term heterocycloalkyl is intended to mean agroup that contains a nonaromatic ring which contains one or more ringhetero (i.e., non-carbon) atoms which are preferably O, N or S, morepreferably N. Also included in the definition of heterocycloalkyl aremoieties that contain exocyclic heteroatoms, for example a cycloalkylring having a ring carbon attached to an exocyclic O or S atom through adouble bond. Also included in the definition of heterocycloalkyl aremoieties that having one or more aromatic rings fused (i.e., having abond in common with) to the nonaromatic heterocyclic ring, for examplephthalimidyl, naphthalimidyl pyromellitic diimidyl, phthalanyl, andbenzo derivatives of saturated heterocycles such as indolene andisoindolene groups.

[0152] As used herein, the term arylsulfonyl is intended to mean amoiety of formula —S(═O)₂-aryl, for example phenylsulfonyl. The termheteroarylsulfonyl means a moiety of formula —S(═O)₂-heteroaryl, forexample pyridinesulfonyl.

[0153] As used herein the term aryloxy is intended to mean an aryl groupattached through an oxygen atom, for example phenoxy.

[0154] As used herein, the term aryloxycarbonyl is intended to men amoiety of formula —C(═O)—O-aryl, for example phenoxycarbonyl.

[0155] As used herein, the term alkoxyalkoxyalkyl is intended to mean amoiety of formula -alkylene-O-alkylene-O-alkyl.

[0156] As used herein, the term hydroxyalkyl is intended to mean analkyl group that has a hydrogen atom thereof replaced with OH.

[0157] As used herein, the term alkoxycarbonyl is intended to mean amoiety of formula —C(═O)—O-alkyl.

[0158] As used herein, the term amino refers to NH₂. The term halogenincludes F, Cl, Br and I. The prefix “halo” is intended to denote ahalogen atom. The term “perhalo” is intended to refer to thesubstitution of all hydrogen atoms for halogen atoms. Thus, the term“perhaloaryl” indicated a fully halogenated moiety, for example apentafouorophenyl radical, and the term “perhaloalkylaryl” would beunderstood to indicate a full halogenated alkylaryl group, for example a2,3,5,6,tetrafluoro-4-trifluoromethyl-phenyl radical.

[0159] In one aspect, the present invention provides dimeric compoundswherein two benzimidazole core structures are joined, preferably at the1-position, by a tether. Thus, in certain embodiments, various moietiesappended to the 1-position of the benzimidazole core can be appended toa benzimidazole core structure at the 1-position thereof.

[0160] As used herein, the term alkoxy means moieties of formula—O-alkyl. The term arylcarbonyl means a moiety of formula —C(═O)-aryl.The term heteroarylcarbonyl means a moiety of formula —C(═O)-heteroaryl.

[0161] The term arylaminocarbonyl means a moiety of formula—C(═O)—NH-aryl. The term cycloalkylaminocarbonyl means a moiety offormula —C(═O)—NH-cycloalkyl.

[0162] The phrase “saturated hydrocarbon fused ring system optionallyhaving an aryl ring fused thereto” is intended to denote saturatedhydrocarbon ring systems having up to three fused rings, for exampledecalin, which can optionally have an aryl ring fused thereto, forexample benzo derivatives of cycloalkyl groups.

[0163] The term arylalkyloxy denotes a froup of formula —O-alkyl-aryl,for example a benzyloxy group. The term alkylheteroaryl denotes a groupof formula -heteroaryl-alkyl, for example a 4-methyl-pyrid-2-yl group.

[0164] The phrase “moiety of formula —OCH₂CH₂—O— attached to adjacentatoms of” is intended to mean that the —OCH₂CH₂—O— oxygen atoms areattached to adjacent atoms an indicated moiety (which preferably is acyclic group) to form a 6 membered fused ring comprising the —OCH₂CH₂—O—group and the two atoms to which it is attached.

[0165] The term methylcarbonyl is intended to denote an acetoyl (i.e.,CH₃C(═O)—) group. The term aminoalkyl denotes a group of formula-alkyl-NH₂.

[0166] The phrase “branched and straight chain polyaminoalkyl” isintended to mean a group of formula —((CH₂)_(n)—NH)_(m)—H wherein n canbe from 1 to 6 and m can be from 2 to about 12, in any one or more ofthe hydrogens attached to nitrogen can be replaced with a group offormula —((CH₂)_(p)—NH)_(q)—H where p is 1 to 6 and q is 1 to 12.

[0167] In some embodiments, compounds of the invention contain simplepolyalchol moieties of formula —CH₂(CHOH)₄CH₂OH. It is intended thateach such group specifically include each individual stereoisomer ofsuch formula, as well as racemic forms of the same.

[0168] In certain embodiments, variables R₁₅ and R₁₆ together with thenitrogen atom to which they are attached can form a nitrogen heterocyclewhich can be aromatic or aliphatic, or aliphatic having one or morearomatic rings fused thereto (i.e., a fused ring derivative). Thus, insome embodiments, R₁₅ and R₁₆ together with the nitrogen atom to whichthey are attached can form, for example, an N-maleimidyl,N-succinimidyl, N-phthalimidyl, N-naphthalimidyl, N-pyromelliticdiimidyl, N-benzopyrrolidinyl, or benzimidazol-1-yl group.

[0169] The term alkylamino is intended to denote a group of formula—NH-alkyl. The term aminoalkylamino is intended to denote a group offormula —NH-alkyl-NH₂. The term poly(aminoalkyl)amino is intended todenote a group of formula —NH-(alkyl-NH)_(x)—H where x is from 2 toabout 12, and wherein any one or more of the hydrogens attached tonitrogen can be replaced with a group of formula ((CH₂)_(p)—NH)_(q)—Hwhere p is 1 to 6 and q is 1 to 12.

[0170] The term heterocycloalkylamino is intended to denote a group offormula —NH-heterocycloalkyl. The term heterocycloalkylalkyl is intendedto denote a group of formula alkyl-heterocycloalkyl).

[0171] The term “side chain of a naturally occurring alpha amino acid”is intended to mean the side chain of naturally occurring alpha aminoacids, with the exception of glycnie, that are known to have the formulaH₂N—CHR—COOH, where R is the side chain. Examples of such naturallyoccurring amino acids include the 20 so called “essential” amino acids,for example serine and threonine. Further side chains of naturallyoccurring alpha amino acids can be found in Bikochemistry, 3rd Edition,Matthews, Van Holde, and Ahern, Addison Wesley Longman, San Francisco,Calif., incorporated by reference herein in its entirety.

[0172] As used herein, the term alkoxyalkoxyalkyl is intended to denotea group of formula alkyl-O-alkyl-O-alkyl. The term hydroxyalkyl isintended to mean a hydroxy group that is substituted with up to 3hydroxy groups. The term heteroarylcarbonyl denotes a moiety of formula—C(═O)-heteroaryl. The term arylaminocarbonyl denotes a moiety offormula —C(═O)—NH-aryl. The term cycloalkylaminocarbonyl denotes amoiety of formula —C(═O)—NH-cycloalkyl.

[0173] The compounds of the present invention and their pharmaceuticallyacceptable salts are useful in for the treatment of bacterial infectionsin animal and human subjects. The compounds of the invention can be usedalone, or in a pharmaceutical composition containing one or morecompounds of the invention, in combination with one or morepharmaceutically acceptable carriers. Thus, in further aspects, thepresent invention includes pharmaceutical compositions and methods oftreating bacterial infections utilizing as an active ingredient thenovel compounds described herein.

[0174] In some embodiments, the compounds of the invention can beprepared as amine salts, which can contain any of a variety ofpharmaceutically acceptable counterions. Suitable counterions includeacetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate,aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate,camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate,glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate,mandelate, methanesulfonate, pantothenate, pectinate,phosphate/diphosphate, polygalacturonate, propionate, salicylate,stearate, succinate, sulfate, tartrate and tosylate. Other suitableanionic species will be apparent to the skilled practitioner.

[0175] Representative examples of compounds of the invention are shownbelow. It is contemplated that the present invention include allpossible protonated and unprotonated forms of the compounds disclosedherein.

[0176] The compounds of the invention can be formulated inpharmaceutical compositions which can include one or more compounds ofthe invention and one or more pharmaceutically acceptable carriers. Thecompounds of the invention can be administered in powder or crystallineform, in liquid solution, or in suspension. They may be administered bya variety of means known to be efficacious for the administration ofantibiotics, including without limitation topically, orally andparenterally by injection (e.g., intravenously or intramuscularly).

[0177] When administered by injection, a preferred route of delivery forcompounds of the invention is a unit dosage form in ampules, or inmultidose containers. The injectable compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, andmay contain various formulating agents. Alternatively, the activeingredient may be in powder (lyophillized or non-lyophillized) form forreconstitution at the time of delivery with a suitable vehicle, such assterile water. In injectable compositions, the carrier is typicallycomprised of sterile water, saline or another injectable liquid, e.g.,peanut oil for intramuscular injections. Also, various buffering agents,preservatives and the like can be included.

[0178] Topical applications may be formulated in carriers such ashydrophobic or hydrophilic bases to form ointments, creams, lotions, inaqueous, oleaginous or alcoholic liquids to form paints or in drydiluents to form powders.

[0179] Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral compositions may utilizecarriers such as conventional formulating agents, and may includesustained release properties as well as rapid delivery forms.

[0180] The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, the sensitivity of the pathogen to the particularcompound selected, the virulence of the infection and other factors.Such matters, however, are left to the routine discretion of thephysician according to principles of treatment well known in theantibacterial arts. Another factor influencing the precise dosageregimen, apart from the nature of the infection and peculiar identity ofthe individual being treated, is the molecular weight of the compound.

[0181] The compositions for human delivery per unit dosage, whetherliquid or solid, may contain from about 0.01% to as high as about 99% ofactive material, the preferred range being from about 10-60%. Thecomposition will generally contain from about 15 mg to about 2.5 g ofthe active ingredient; however, in general, it is preferable to employdosage amounts in the range of from about 250 mg to 1000 mg. Inparenteral administration, the unit dosage will typically include thepure compound in sterile water solution or in the form of a solublepowder intended for solution, which can be adjusted to neutral pH andisotonic.

[0182] The invention described herein also includes a method of treatinga bacterial infection in a mammal in need of such treatment comprisingadministering to said mammal a compound of the invention in an amounteffective to treat said infection. One preferred method ofadministration of the antibacterial compounds of the invention includeoral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection.

[0183] Compounds provided herein can be formulated into pharmaceuticalcompositions by admixture with pharmaceutically acceptable nontoxicexcipients and carriers. As noted above, such compositions may beprepared for use in parenteral administration, particularly in the formof liquid solutions or suspensions; or oral administration, particularlyin the form of tablets or capsules; or intranasally, particularly in theform of powders, nasal drops, or aerosols; or dermally, via, forexample, transdermal patches; or prepared in other suitable fashions forthese and other forms of administration as will be apparent to thoseskilled in the art.

[0184] The composition may conveniently be administered in unit dosageform and may be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980). Formulationsfor parenteral administration may contain as common excipients sterilewater or saline, polyalkylene glycols such as polyethylene glycol, oilsand vegetable origin, hydrogenated naphthalenes and the like. Inparticular, biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers may be useful excipients to control the release of the activecompounds. Other potentially useful parenteral delivery systems forthese active compounds include ethylene-vinyl acetate copolymerparticles, osmotic pumps, implantable infusion systems, and liposomes.Formulations for inhalation administration contain as excipients, forexample, lactose, or may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for parenteral administration mayalso include glycocholate for buccal administration, a salicylate forrectal administration, or citric acid for vaginal administration.Formulations for transdermal patches are preferably lipophilicemulsions.

[0185] The materials of this invention can be employed as the soleactive agent in a pharmaceutical or can be used in combination withother active ingredients, e.g., other growth factors which couldfacilitate neuronal survival or axonal regeneration in diseases ordisorders.

[0186] The concentrations of the compounds described herein in atherapeutic composition will vary depending upon a number of factors,including the dosage of the drug to be administered, the chemicalcharacteristics (e.g., hydrophobicity) of the compounds employed, andthe route of administration. In general terms, the compounds of thisinvention may be provided in effective inhibitory amounts in an aqueousphysiological buffer solution containing about 0.1 to 10% w/v compoundfor parenteral administration. Typical dose ranges are from about 1mg/kg to about 1 g/kg of body weight per day; a preferred dose range isfrom about 0.01 mg/kg to 100 mg/kg of body weight per day. Suchformulations typically provide inhibitory amounts of the compound of theinvention. The preferred dosage of drug to be administered is likely,however, to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, and formulation of the compound excipient, and its route ofadministration.

[0187] As used herein, the term “contacting” means directly orindirectly causing at least two moieties to come into physicalassociation with each other. Contacting thus includes physical acts suchas placing the moieties together in a container, or administeringmoieties to a patient. Thus, for example administering a compound of theinvention to a human patient evidencing a disease or disorder associatedwith abnormal and/or aberrant activity of such proteases falls withinthe scope of the definition of the term “contacting”.

[0188] Compounds of the invention also are useful for in silico studiesto determine potential binding to binding pockets present in a varietyof bacteria, including those disclosed in the Examples herein. Thus, thepresent invention further provides methods for determining bindingaffinities for classes of compounds in silico. In the methods,representations of the compounds of the invention can be used inmolecular modeling studies to determine such binding affinities, andtherefore aid in the design of therapeutics.

[0189] While the present invention has been described with specificityin accordance with certain of its preferred embodiments, the followingexamples serve only to illustrate the invention and are not intended tolimit the same.

EXAMPLES Example 1

[0190] General Procedure for Preparation of Benzimidazoles HavingModification to the Phenyl (B) Ring

[0191] The general procedure for preparation of benzimidazoles havingmodification to the phenyl (B) ring is shown in Scheme 1, below:

[0192] Generally, the steps of the synthesis are:

[0193] (1) N-Boc isonipecotic acid (25 g, 109 mmol) was dissolved in DMF(500 mL). HATU (49.5 g, 130 mmol) was added, followed by DMAP (16.0 g,150 mmol) and DIEA (45 mL, 260 mmol). After the mixture was stirred for30 minutes, diamine (105 mmol) was added and the resulting reactionmixture stirred overnight. The mixture was concentrated to one fourth ofthe volume, and poured into brine, extracted with dichloromethane (3×150mL). The combined organic solution was dried over magnesium sulfate andconcentrated too give black oil.

[0194] (2) The black oil was dissolved in ethanol (250 mL) and 2 Msodium hydroxide (250 mL). The mixture was refluxed overnight, cooled toroom temperature and poured into saturated citric acid solution. Theresulting mixture was extracted with dichloromethane (4×150 mL), and thecombined organic solution was dried over magnesium sulfate andconcentrated too give a black oil, which was purified on silica gel withethyl acetate and dichloromethane to give the desired product.

[0195] (3) N-Boc compound (0.02 mmol) was placed in a 2-drum vial with astirbar, and hydrochloric acid in dioxane (6.0 M, 500 L) was added. Themixture was stirred at room temperature for 30 minutes to give thecorresponding product as precipitate (hydrochloride salt). The mixturewas centrifuged, the solution removed using a pipette, and the solidsalt was dried under vacuum overnight.

[0196] (4) 4-Nitro Benzimidazole hydrochloride salt (0.02 mmol),prepared by the procedure above was dissolved in methanol (2.0 mL),followed by the addition of palladium on carbon (10%, 5 mg). Theresulting mixture was hydrogenated with a hydrogen balloon at roomtemperature for two hours. The catalyst was filtered off and washed withmethanol (3×1.0 mL). The combined methanol solution was concentrated anddried under vacuum overnight.

[0197] (5) N-Boc benzimidazole (0.04 mmol) was dissolved in formic acid(1.0 mL) and formaldehyde (1.0 mL, 37%), and the mixture was heated at120° C. with an oil bath for 3 hours. Ethyl acetate (5.0 mL) was added,followed by excess solid sodium bicarbonate to neutralize the acid. Themixture was extracted with ethyl acetate (4×5 mL), and the combinedorganic solution was dried over magnesium sulfate and concentrated toogive the crude product, which was purified on silica gel with methanolin chloroform (5%, 10% and 20%, 20%) and 2% NH₃▪H₂O and 20% MeOH inCHCl₃. (1694-5)

[0198]¹H NMR (200 MHz, CDCl₃): 8.44 (s, 1H), 8.12 (d, J=9.0 Hz, 1H),7.56 (d, J=9.0 Hz, 1H) 3.60-3.40 (m, 1H), 3.20-2.90 (m, 2.H), 2.35 (s,3H), 2.30-2.00 (m, 5) LC/MS: M+H⁺=261

[0199] (6) 4-Nitro Benzimidazole from step (4) (0.02 mmol) was dissolvedin methanol (2.0 mL), followed by the addition of palladium on carbon(10%, 5 mg). The resulting mixture was hydrogenated with a hydrogenballoon at room temperature for two hours. The catalyst was filtered offand washed with methanol (3×1.0 mL). The combined methanol solution wasconcentrated and dried under vacuum overnight.

Example 2

[0200] General Procedure for Synthesis of Benzimidazoles HavingModification to the Imidazole (A) Ring

[0201] The general procedure for preparation of benzimidazoles havingmodification to the imidazole (A) ring is shown in Schemes 2 and 3,below:

[0202] Aryl diamines (1.0 mmol) and isonipecotic acid (129 mg, 1.2 mmol)were grounded into powder and well mixed. Polyphosphoric acid (PPA, 1.0g) was then added. The mixture was heated in an oil-bath at 180° C. fortwo hours. The syrup was cooled to room temperature, and saturatedsodium hydroxide was added to make the resulting mixture basic. Themixture was extracted with 30% isopropanol in chloroform (5×30 mL), andthe combined organic solution was dried over magnesium sulfate andconcentrated. The crude product was then purified by silica gelchromatography using methanol in chloroform (5%, 10% and 15%).

[0203] Rf=0.15 (2% NH₃▪H₂O and 20% ¹PrOH in CHCl₃) LC/MS: M+H⁺=202 (2Gcolumn) ¹H NMR (200 MHz, CDCl₃): 7.55-7.44 (m, 2H), 7.23-7.13 (m 2H),3.34-2.98 (m, 3), 2.83-2.66 (m, 2H), 2.14-2.00 (m, 2H), 1.96-1.72 (m,2H).

[0204] (1) Sodium hydride (24 mg, 60%, 1 mmol) was washed with hexane(3×1 mL). Anhydrous CH₃CN (2.0 mL) was added, followed byN-Boc-4,5-dichlorobenzimidazole (37 mg, 0.1 mmol) portion wise underargon. After the slurry was stirred at room temperature for 30 minutes,the alkylating halide (0.15 mmol) was added, and the reaction mixturewas stirred at room temperature for another 30 minutes (The reactionprogress was monitored by TLC). The reaction was cooled with an icebath, and ice water (2.0 mL) was carefully added. The resulting crudemixture was extracted with ethyl acetate (3×10 mL), the combined organicsolution was washed with brine (2×2 mL) and dried over magnesium sulfateand concentrated. The crude product was then purified by silica gelchromatography using ethyl acetate in hexane (10%, 20% and 30%).

[0205] Yield: 95% Rf=0.15 (2% NH₃▪H₂O and 20% ¹PrOH in CHCl₃) LC/MS:M+H⁺=516 (2CN column) ¹H NMR (200 MHz, CD₃OD): 7.29 (s, 1H), 7.62 (s,1H), 7.42-7.40 (m, 2H), 7.05-6.85 (m, 2H), 5.5 (s, 2H), 4.20-4.02 (m,2H), 3.25-3.10 (m, 1H), 2.92-2.72 (m, 2H), 1.45 (s, 9H), 1.28 (s, 3H).

[0206] (2) N-Boc compound (0.02 mmol) was placed in a 2-drum vial with astirbar, and hydrochloric acid in dioxane (6.0 M, 500 L) was added. Themixture was stirred at room temperature for 30 minutes to give thecorresponding product as precipitate (hydrochloride salt). The mixturewas centrifuged, the solution removed using a pipette, and the solidsalt was dried under vacuum over night.

[0207] Yield: 90% LC/MS: M+H⁺=202 (2G column)

Example 4

[0208] General Procedure for Preparation of Benzimidazole Derivativesvia Solid Phase Synthesis

[0209] The general procedure for preparation of benzimidazolederivatives via solid phase synthesis is shown in Scheme 4, below:

[0210] (1) N-Boc-4,5-dichlorobenzimidazole (3.0 mg, 10.7 mmol) waspowdered and treated with hydrogen chloride in dioxane (6 N) for 2 h.Dioxane was then evaporated and the corresponding hydrochloride salt wasdried under vacuum overnight, which was directly used to attach to theWang resin

[0211] (2) Wang resin (15.0 g, 5.70 mmol) (Sigma-Aldrich 2000-2001Catalog, item # 47,703-6) was swollen in DMF (120 mL), and carbonyldiimidazole (1.84 g, 11.4 mmol) was added and the resulting mixturestirred at room temperature overnight. The resin was filtered off andwashed successively with DMF (3×30 mL), dichloromethane (3×30 mL),diethyl ether (3×30 mL) and dried overnight. The resulting resin wasagain suspended in DMF (200 mL), all the benzimidazole hydrochloridesalt obtained in step (1) was added, followed by triethylamine (3.0 mL,21.6 mmol). The resulting mixture was stirred at room temperatureovernight. The resin was filtered off and washed successively with DMF(3×30 mL), dichloromethane (3×30 mL), methanol (3×30 mL), diethyl ether(3×30 mL) and dried overnight.

[0212] (3) Benzimidazole on Wang resin obtained in step (2) (100 mg,0.0324 mmol) was suspended in DMF (2.0 mL), sodium hydride (60%, 50 mg,1.25 mmol) was added and the mixture stirred for 15 minutes at roomtemperature. Alkylating halide (0.0972 mmol) was added, and the mixturewas stirred for 2 hours at room temperature. The reaction flask was thencooled with ice bath, and water (100 L) was carefully added to reactwith the excess sodium hydride. The resin was filtered off and washedsuccessively with water ((3×1.0 mL), DMF (3×1.0 mL), dichloromethane(3×3=1.0 mL), methanol (3×1.0 mL), diethyl ether (3×1.0 mL) and driedovernight.

[0213] (4) The resin obtained in step (3) was suspended indichloromethane (1.4 mL), trifluoroacetic acid (600 L) was added and themixture was gently stirred for 30 minutes at room temperature. The resinwas then filtered off and washed with dichloromethane (5×1.0 mL). Thedichloromethane solution was dried to give the benzimidazoles astrifluoroacetic acid salt.

Example 5

[0214] General Procedure for Preparation of Xylene-1-yl BenzimidazoleDerivatives via Solid Phase Synthesis

[0215] The general procedure for preparation of xylene-1-ylbenzimidazole derivatives via solid phase synthesis is shown in Scheme5, below:

[0216] (1) Benzimidazole on Wang resin (2.0 g, ˜0.65 mmol) was suspendedin DMF (20.0 mL), saturated potassium carbonate (2.0 mL) was added,followed by α,α′-dibromo-p-xylene (860 mg, 3.25 mmol), and the resultingmixture was gently stirred at room temperature for 5 hours. The resinwas filtered off and washed successively with water ((3×1.0 mL), DMF(3×10.0 mL), dichloromethane (3×3=10.0 mL), methanol (3×10.0 mL),diethyl ether (3×10.0 mL) and dried overnight.

[0217] (2) Benzyl bromide on resin obtained instep (1) (100 mg, 0.0324mmol) was suspended in DMF (2.0 mL), and amine (0.324 mmol) was added.The reaction mixture was gently stirred at room for six hours. The resinwas filtered off and washed successively with DMF (3×1.0 mL),dichloromethane (3×3=1.0 mL), methanol (3×1.0 mL), diethyl ether (3×1.0mL) and dried overnight.

[0218] (3) The resin obtained in step (1) was suspended indichloromethane (1.4 mL), trifluoroacetic acid (600 L) was added and themixture was gently stirred for 30 minutes at room temperature. The resinwas then filtered off and washed with dichloromethane (5×1.0 mL). Thedichloromethane solution was dried to give the benzimidazoles astrifluoroacetic acid salt.

Example 6

[0219] General Procedure for Preparation of Benzimidazole DerivativesHaving Urea or Thiourea Functionality

[0220] The general procedure for preparation of benzimidazolederivatives having urea or thiourea functionality is shown below inScheme 6:

[0221] (1) To a solution of N-Boc benzimidazole (200 mg, 0.54 mmol) inDMF (2.0 mL) was added sodium hydride (60%, 65 mg, 1.40 mmol)portion-wise, and the resulting mixture was stirred for 20 minutes.Methyl bromoacetate (214 mg, 1.40 mmol) was then added and the reactionmixture was stirred at room temperature for 2 hours. The reaction flaskwas then cooled with ice bath, and water (100 μL) was carefully added toreact with the excess sodium hydride. The resulting mixture was thendiluted with ethyl acetate (30 mL), washed with brine (5×2 mL) and driedover magnesium sulfate. The crude product was purified on silica gelwith 50% ethyl acetate in hexane to give 210 mg (88%) of the desiredmethyl ester. (1815-41)

[0222] Rf=0.40 (AcOEt:Hexane=1:1) LC/MS: M+H⁺=442 (2CN column) ¹H NMR(200 MHz, CDCl₃): 7.80 (s, 1H), 7.38 (s, 1H), 4.95 (s, 2H), 4.40-4.15(m, 3H), 3.78 (s, 3H), 3.00-2.78 (m, 2H), 2.10-1.80 (m, 6 H).

[0223] (2) To the solution of methyl ester (160 mg, 0.36 mmol) obtainedform step 1) in methanol (5.0 mL) was added hydrazine (46.0 mg, 1.44mmol), and the resulting mixture was stirred at room temperature forthree hours. The reaction was then concentrated and the crude productpurified on silica gel with 10% methanol in chloroform to give thecorresponding acyl hydrazine (152 mg, 92%) Rf=0.15 (MeOH: CHCl₃=1:1)

[0224] (3) To the solution of acyl hydrazine (30 mg, 0.068 mmol)obtained from step 2) in chloroform (2.0 mL) was added isocynate orisothiocynate (0.068 mmol) at 0C., and the reaction was warmed up andstirred at room temperature for one hour. TLC and LC/MS indicatedcomplete conversion of the starting material and the product has morethan 90% purity.

[0225] (4) Urea or thiourea (0.02 mmol) obtained in step 3) was powderedand treated with hydrogen chloride in dioxane (6 N) for 2 h. Dioxane wasthen evaporated and the corresponding hydrochloride salt was dried undervacuum overnight. LC/MS indicated complete conversion of startingmaterial and desired product has over 90% purity.

Example 7

[0226] General Procedure for Preparation of Benzimidazole DerivativesHaving Hydrazone Functionality

[0227] The general procedure for preparation of benzimidazolederivatives having hydrazone functionality si shown below in Scheme 7:

[0228] (1) To the solution of acyl hydrazine (20 mg, 0.045 mmol) andaldehyde (0.0475 mmol) in THF (1.0 mL) was added catalytic amount ofp-tolunesulfonic acid. The reaction mixture was stirred at roomtemperature for two hours, and dried. TLC and LC/MS indicated completeconversion of starting material and desired product has over 90% purity.

[0229] (2) Half of the N-Boc hydrazone obtained above (0.023 mmol) waspowdered and treated with hydrogen chloride in dioxane (6 N) for 30 min.Dioxane was then evaporated and the corresponding hydrochloride salt wasdried under vacuum overnight. LC/MS indicated complete conversion ofstarting material and desired product has over 90% purity.

Example 8

[0230] General Procedure for Preparation of Benzimidazole DerivativesHaving Sulfonamide Functionality

[0231] The general procedure for preparation of benzimidazolederivatives having sulfonamide functionality si shown below in Scheme 7:

[0232] (1) To the solution of acyl hydrazine (20 mg, 0.045 mmol) andpyridine (6.0 mg, 0.072 mmol) and DMAP (catalytic) in 30% THF in CH₂Cl₂was added sulfonyl chloride (0.0475 mmol). The reaction mixture wasstirred at room temperature overnight, and dried. TLC and LC/MSindicated complete conversion of starting material and desired producthas over 90% purity.

[0233] (2) Half of the N-Boc sulfonamide obtained above (0.023 mmol) waspowdered and treated with hydrogen chloride in dioxane (6 N) for 2 h.Dioxane was then evaporated and the corresponding hydrochloride salt wasdried under vacuum overnight. LC/MS indicated complete conversion ofstarting material and desired product has over 90% purity.

Example 9

[0234] General Procedure for Preparation of Benzimidazole DerivativesHaving Substituted Alkyl Functionality

[0235] The general procedure for preparation of benzimidazolederivatives having substitutued alkyl functionality is shown below inScheme 9. While the procedure is illustrated for phthalimidyl-alkylfunctionalization, the procedure is generally applicable to to thepreparation of benzimidazoles having a wide variety of heterocyclesattached through alkyl spacers.

[0236] (1) To the solution of N-Boc benzimidazole (110 mg, 0.30 mmol),and diiodide (1.50 mmol) in DMF (3.0 mL) was added sodium hydride (60%,120 mg, 3.0 mmol) portion-wise. After the reaction mixture was stirredat room temperature for 20 minutes, the reaction flask was then cooledwith ice bath, and water (100 mL) was carefully added to react with theexcess sodium hydride. The resulting mixture was then extracted withethyl acetate (3×10 mL) and the combined organic solution was Washedwith brine and dried over magnesium sulfate. The crude product waspurified on silica gel with 50% ethyl acetate in hexane.

[0237] Rf=0.55 (AcOEt:Hexane=1:1) LC/MS: M+H⁺=567 (2CN column) ¹H NMR(200 MHz, CDCl₃): 7.75 (s, 1H), 7.35 (s, 1H), 4.35-4.15 (m, 1H),4.20-3.95 (m, 2H), 3.20-3.00 (m, 2H), 2.00-1.20 (m, 12 H).

[0238] (2) To the solution of iodo benzimidazole obtained in step 1)(0.044 mmol), phthalimide or amide (0.066 mmol) in DMF (1.5 mL) wasadded potassium carbonate (11 mg, 0.066 mmol). After being stirred atroom temperature overnight, the reaction mixture was diluted with 50 mLof ethyl acetate, washed with brine (5×2 mL), dried over magnesiumsulfate and concentrated. The crude product was purified on silica gelwith 50% ethyl acetate in hexane.

[0239] Rf=0.40 (AcOEt:Hexane=1:1) LC/MS: M+H⁺=631 (2CN column) ¹H NMR(200 MHz, CDCl₃): 8.70-8.55 (m, 3H), 8.10-8.00 (m, 1H), 7.78 (s, 1H),7.41 (s, 1H), 4.40-4:00 (m, 3H), 3.82-3.70 (m, 2H), 3.08-2.80 (m, 2H),2.00-1.20 (m, 12 H).

Example 10

[0240] Biological Evaluation of Compounds

[0241] Compounds were evaluated for in vitro antibacterial activity(referred to MIC, the minimum concentration inhibiting fungal cellgrowth) against S. aureus and E. coli. Table 2 shows the in vitroinhibitorial activity of selected benzimidazoles against additionalpathogenic strains of bacteria (four Gram positive strains, four gramnegative strains and one yeast strain). The assays are carried out in150 mL volume in duplicate in 96-well clear flat-bottom plates. Thebacterial or yeast suspension from an overnight culture growth inappropriate medium is added to a solution of test compound in 2.5% DMSOin water. Final bacterial or yeast inoculum is approximately 10²-10³CFU/well. The percentage growth of the bacteria or yeast in test wellsrelative to that observed for a control well containing no compound isdetermined by measuring absorbance at 595 nm (A₅₉₅) after 20-24 hours at37° C. (bacteria) or 40-48 hours (yeast) at 25° C. The MIC is determinedas a range of concentration where complete inhibition of growth isobserved at the higher concentration and bacterial/yeast cells areviable at the lower concentration. Ampicillin and tetracycline are usedas antibiotic positive controls for bacterial MIC assays. Amphotericin Bis used as a positive control for yeast MIC assay.

Example 11

[0242] Preparation of 5,6-dichloro-2-piperidin-4-yl BenzimidazoleDerivatives

[0243] Using the procedures described above, the following5,6-dichloro-2-piperidin-4-yl benzimidazole derivatives preparedaccording to Scheme 11 as described below:

[0244] Treatment of commercially available4,5-dichloro-1,2-phenylenediamine (VENDOR?) (1) and N-Boc-isonipecoticacid (2) with EDC in the presence of catalytic amount of DMAP led to theformation of the corresponding amide. The crude mixture was thenrefluxed in aqueous sodium hydroxide solution to give cyclizedintermediate 3, which was reacted with various alkyl, benzyl and arylhalides to give 4a-4l. Treatment of compound 4g with various amines ornitrogen-containing heterocylces provided 6a-x. Deprotection of the Bocgroup with anhydrous hydrogen chloride (HCl, 4.0 M) in dioxane at roomtemperature for 30 minutes to form benzimidazoles 7a-x. In a similarmanner, 4a-4l were treated with hydrogen chloride to give benzimidazoles5a-i.

[0245] This procedure was employed to prepare the following compounds:5a R = H 5b R = Et 5c R = 4-PyCH2 5d R = 3-PyCH2 5e R = 4-F-Bn 5f R =4-NO2-Bn 5g R = 4-(BrCH2)Bn 5h R = 2-Pyrimidine 5i R = 2,4-(NO2)2Ph 6/7a

6/7b

6/7c

6/7d

6/7e

6/7f

6/7g

6/7h

6/7i

6/7j

6/7k

l

m

n

o

p

q

r

s

t

u

v

w

x

[0246] These compounds were evaluated for their ability to inhibit S.aureus and E. coli growth and Bacterial Transcription/Translationaccording to the procedures described herein. In addition, allbenzimidazoles were also screened for their ability to inhibit bacterialtranslation and transcription using a combined assay. Several compounds(7c, 7d, 7j-l, 10a-b) were found to posses low micromolar IC50. Sincemost of the IC50 value are much higher than the corresponding MICs forS. aeures and E. coli., it's unlikely that the antibacterial activitiesare the direct results of bacterial transcription/translationinhibition. However they could be a result from the combination ofmultiple mechanisms of actions including transcription/translationinhibition. The results are presented in Table 1 below: TABLE 1Inhibitory Effects of Benzimidazoles on S. aureus and E. coli Growth andBacterial Transcription/Translation. S. aureus E. coli T/T IC50Compounds MIC (μM) MIC (μM) MIC (μM) (5a) >100 >100 >100(5b) >100 >100 >100 (5c) 75.00 94 >100 (5d) 75.00 86 >100(5e) >100 >100 >100 (5f) >100 >100 >100 (4g) 52.00 >100 >100(5h) >100 >100 >100 (5i) >100 >100 >100 (7a)  6-12 12-25 100 (7b) 3-6 6-12 >100 (7c)  6-12 12-25 12 (7d) 12-25  50-100 20 (7e)  6-12 25-50 50(7f) 12-25 25-50 >100 (7g)  6-12 12-25 100 (7h) 12-25  50-100 >100 (7i) 6-12  6-12 >100 (7j)  6-12  50-100 10 (7k) 3-6 25-50 10 (7l) 3-6 12-2510 (7m)  6-12 12-25 >100 (7n) 12-25 12-25 >100 (7o)  6-12 12-25 25 (7p)12-25 12-25 >100 (7q) — — — (7r)  6-12 12-25 >100 (7s)  6-12 12-25 >100(7t)  6-12  50-100 60 (7u)  6-12 25-50 >100 (7v) >100 >100 12-25 (7w)12-25 12-25 >100 (7x)  6-12  6-12 >100 (10a) 25-50 25-50 25 (10b) 12-2512-25 35 (10c)  6-12 12-25 >100 (12) 3-6  6-12 >100

Example 12

[0247] Preparation of Benzimidazole Dimers

[0248] Several benzimidazole dimers were prepared according to theprocedures of Schemes 12 and 13, below, and evaluated for theirantibacterial activity.

Synthesis of Benzimidazole Dimers 10a-c

[0249] Reagents and conditions: a) NaH, DMF, 0° C., 2 h,1,3-diiodopropane, 8a, 54%; 1,5-diodopentane, 8b, 66%; 1,6-diodohexane,8c, 70%; (b) 3, NaH, DMF, 0° C., 2 h, 61% for 9a, 65% for 9b, 62% for9c; (c) 6 MHCl/dioxane, 25° C., 2h.

Synthesis of Benzimidazole Dimer 12

[0250] Reagents and conditions: a) 0.5 equiv. α,α-dibromo-p-xylene, NaH,DMF, 0° C., 2 h, 56%; (b) 4 M HCl/dioxane, RT, 2h, 98%.

[0251] Mono alkylation of benzimidazole with diiodo alkanes providedintermediates 8a-c, which were then reacted again with 3 to provide thecorresponding dimers 9a-c. The Boc protecting groups were cleanlyremoved using hydrogen chloride in dioxane to give the final dimeranalogs 10a, 10b and 10c in almost quantitative yield (Scheme 12). Thexylene-spaced dimer 12 was prepared from intermediate 3 by firstreacting 0.5 equivalents of α,α-dibromo-p-xylene (11), followed bydeprotection using hydrogen chloride (Scheme 13).

[0252] The inhibitory effects of benzimidazole dimers on S. aureus andE. coli growth and bacterial transcription/translation are shown inTable 2 below. TABLE 2 Inhibitory Effects of Benzimidazole Dimers on S.aureus and E. coli Growth and Bacterial Transcription/Translation. S.aureus E. coli T/T IC50 Compounds MIC (μM) MIC (μM) MIC (μM) (10a) 25-5025-50 25 (10b) 12-25 12-25 35 (10c)  6-12 12-25 >100 (12) 3-6  6-12 >100

[0253] To test effectiveness of benzimidazoles of Examples 11 and 12against other bacteria, the active compounds from the preliminaryscreening were screened against additional four strains of Gram positiveand four strains of gram negative bacteria, and the results are shown inFIG. 1. These compounds exhibited higher potencies against Gram positionbacteria (S. aureus 13709, E. hirae 29121, S pyogenes 49399, and S.pneumoniae 6303) as compared to Gram-negative bacteria (E. coli 25922,P. vulgaris 8427, K. pneumoniae 1338, P. aeruginosa 25416). Severalbenzimidazoles (7b, 7g-k, 12) showed particularly strong activityagainst E. hirae. To study the selectivity, these compounds were alsoscreened against yeast cell line C. albicans 10231. These compounds areclearly much less effective as compared to their inhibition of bacterialgrowth.

[0254] Since entercocccus infection is upcoming, and presents a majorthreat to the human health, compounds were screened against sevenadditional clinically important strains of entercocccus and the resultsare shown in FIG. 2. As mentioned previously, all these selectedcompounds are very effective against E. Hirae_ATCC_(—)29212 and lesspotent against other strains with some exceptions that six of them (7a,7b, 7x, 10b, 10c, 12) exhibited strong inhibitory activities against alleight strains.

Example 13

[0255] Preparation of Alkyl Spaced Benzimidazole Derivatives

[0256] Several alkyl spaced benzimidazole derivatives were preparedaccording to the procedures of Scheme 14, below:

Alkyl Spaced Benzimidazole Derivatives

[0257] Reagents and conditions: a) EDC, DMAP; b). NaOH, H₂O, 65% over 2steps; c) ICH_(n)(CH_(n))_(n)CH_(n)I, NaH or K₂CO₃; d) ArH, NaH orK₂CO₃; e) 4.0 M HCl/dioxane, CH₂Cl₂, 25° C., 0.5 h, >95%.

[0258] 4,5-dichloro-1,2-dianiline (1) reacted smoothly withN-Boc-isonipecotic acid to give the corresponding amide, which cyclizedupon treatment with sodium hydroxide to give benzimidazole 5. Reactionof 5 with different diiodides furnished 6-10 in good yields. A varietyof nitrogen-containing heterocylces were then introduced by simplealkylation to give the target molecules 11-15.

Example 14

[0259] Preparation of Hydrazone Benzimidazole Derivatives

[0260] Several hydrazone benzimidazole derivatives were preparedaccording to the procedures of Scheme 15 below:

Preparation of Hydrazone Benzimidazole Derivatives

[0261] Reagents and conditions: a). NaH (3.0 equiv), BrCH₂CO₂Me (1.2equiv), DMF, 25° C., 0.5 h, 92%; B). H₂NNH₂ (5.0 equiv), DMF, 25° C.,2.0 h, 98%; c). ArCHO (1.02 equiv), CH₂Cl₂, 25° C., 0.5 h, >95%; d). 4.0M HCl/dioxane, CH₂Cl₂, 25° C., 0.5 h, >95%.

[0262] Acylhydrazide 17 was synthesized as a key intermediate for thecombinatorial generation of benzimidazoles. Since the acyl hydrazidecould serve as both a hydrogen donor and acceptor to add additionalcontacts with the target, analogs based on 17 could be potentially morepotent than the parent benzimidazoles. Acycl hydrazide 17 was easilyprepared from 3 in gram quantity in excellent overall yield from 5 byalklylation with methyl α-bromoacetate followed by a nucleophilicdisplacement of the methoxy group. Many derivatives could be easilysynthesized form 17 without the need of vigorous purification. The firstseries of analogs has the general structure 18 and was prepared bysimply reacting 17 with different aldehydes followed by the removal ofthe Boc protecting group with hydrogen chloride. All the benzimidazoleanalogs obtained this way have more than 95% purity based on TLC andLC/MS analysis and were used directly for our MS-based screening andantibacterial assays.

Example 15

[0263] Preparation of Hydrazine Benzimidazole Derivatives

[0264] Several hydrazine benzimidazole derivatives were preparedaccording to the procedures of Scheme 16 below:

Hydrazine Benzimidazole Derivatives

[0265] Synthesis of Benzimidazoles 19a-19y. Reagents and conditions: a)For 19a-o, RNCO or RNCS (1.05 equiv), CH₂CH₂, 25° C., 0.5 h, >95%.; for19p-y, RSO₂Cl (1.05 equiv), Et₃N (1.5 equiv), DMAP (cat.), >95%; b) 4.0M HCl/dioxane, CH₂Cl₂, 25° C., 0.5 h, >95%.

[0266] A variety of isocynates, isothiocyanates and sulfonyl chlorideswere reacted with acyl hydrazide 17, and the corresponding ureas,thioureas and sulfonates were obtained in excellent yields and purity asshown in Scheme 16. The resulting N-Boc protected intermediates weretreated with hydrogen chloride to give the corresponding products ofgeneral structure 19 in almost quantitative yields and more than 95%purity. These products were used directly for antibacterial assays.

Example 16

[0267] Inhibitory Effects of Benzimidazoles on S. aureus and E. coliGrowth and Bacterial Transcription/Translation For Compounds of Examples13-15.

[0268] Table 3 shows the in vitro antibacterial activity (referred to asMIC, the minimum concentration inhibiting fungal cell growth) of thebenzimidazoles against S. aureus and E. coli. FIG. 3 shows the in vitroinhibitorial activity of selected benzimidazoles against additionalpathogenic strains of bacteria (four Gram positive strains, four gramnegative strains and one yeast strain). The assays are carried out in150 μL volume in duplicate in 96-well clear flat-bottom plates. Thebacterial or yeast suspension from an overnight culture growth inappropriate medium is added to a solution of test compound in 2.5% DMSOin water. Final bacterial or yeast inoculum is approximately 10²-10³CFU/well. The percentage growth of the bacteria or yeast in test wellsrelative to that observed for a control well containing no compound isdetermined by measuring absorbance at 595 nm (A₅₉₅) after 20-24 hours at37° C. (bacteria) or 40-48 hours (yeast) at 25° C. The MIC is determinedas a range of concentration where complete inhibition of growth isobserved at the higher concentration and bacterial/yeast cells areviable at the lower concentration. Ampicillin and tetracycline are usedas antibiotic positive controls for bacterial MIC assays. Amphotericin Bis used as a positive control for yeast MIC assay. TABLE 3 InhibitoryEffects of Benzimidazoles on S. aureus and E. coli Growth and BacterialTranscription/Translation. S. aureus E. coli Compound MIC (mM) MIC (mM)6 >100 >100 11 >100 >100 12 >100 >100 13a >100 >100 13o >100 >100l3p >100 >100 14a 12-50 25-50 14b  6-12 >100 14c  50-100 25-50 14d 12-25 50-100 14e >100  50-100 14f >100 >100 14g 25-50  50-100 14h >100 >10014i >100 >100 14j >100 >100 14k >100 >100 14l >100 >100 14l  50-100 50-100 14q >100 >100 15a >100 >100 18a 12-25 >100 18b 12-25 >100 18c25-50 >100 18d 25-50 >100 18e 25-50 >100 18f 25-50 >100 18h 25-50 >10018i 25-50 >100 18j 3-6 >100 18k  50-100 >100 18l  50-100 >100 18m 6-12 >100 18n >100 >100 18o >100 >100 18p >100 >100 18q 25-50 >100 19b12-25 25-50 19c 25-50 >100 19c 12-25 25-50 19d 25-50  50-100 19e 50-100 >100 19f  6-12 12-25 19g  6-12 12-25 19h  6-12 25-50 19h 50-100 >100 19i 25-50  50-100 19j  50-100 >100 19k >100 >10019l >100 >100 19m >100 >100 19o 25-50 25-50 19p 12-25 >100 19q 50-100 >100 19r >100 >100 19s >100 >100 19t >100 >100 19u >100 >10019v >100 >100 19w >100 >100 19x >100 >100 19y >100 >100

Example 17

[0269] Synthesis of Piperidine Modified Benzimidazoles and their BindingAffinities For E. coli 16S A-site

[0270] It has been established that the 16S A-site is involved inbacterial translation, and the aminoglycosides are known to bind to theregion. Thus, the bacterial 16S A-site represents a prime target fordiscovering antibacterial agents, and much work has focused on themodification of the natural aminoglycosides. In accordance with thepresent invention, several small molecules were synthesized that wereshown to bind to the 16S A-site of E. coli ribosome RNA. These are shownbelow in Scheme 17.

Synthesis of piperidine-modified benzimidazoles and their bindingaffinities for E. coli 16S A-site

[0271] MS-based competition experiments were used to determine thebinding location of 1 to the target RNA. Glucosamine is the A-ring ofparomomycin that is known to bind to the target RNA and inhibitsbacterial translation. Data suggest that 1 and glucosamine compete forthe same binding site on the target RNA. Since glucosamine binds to thetarget RNA at the same location as it is in paromomycin binding, whilenot wishing to be bound by any particular theory, it is believed the 1binds to the desired RNA decoding region and could potentially inhibitbacterial translations.

[0272] After establishing the binding of 1 to the correct location onthe target RNA, systematic chemical modifications were carried out tostudy the structure activity relationship (SAR) around thebenzimidazole. The synthesis of compound 1 and piperidine-modifiedbenzimidazoles are shown above in Scheme 17. Treatment of commerciallyavailable 5-nitro-1,2-dianiline (2) and N-Boc-isonipecotic acid (3) withEDC in the presence of catalytic amount of DMAP led to the formation ofthe corresponding amide as a mixture of two regioisomers (4a,b). Thecrude mixture was then refluxed in aqueous sodium hydroxide solution for?? hours gave the cyclized intermediate 6a. Treatment of compound 5 with20% TFA in dichloromethane at room temperature for 30 minutes led to theformation of compound 6, which was then hydrogenated over Pd/C togive 1. MS-based assay suggested that an electron withdrawing nitrogroup at C5 position (6) is preferred over the corresponding amino group(1), and almost doubled the binding affinity for the target 16S RNAA-site. Thus, in order to establish the SAR of the benzimidazoles, aseries of piperidine-modified analogs with a nitro substitution at 5position (6a-7b) were synthesized by following the same synthetic routeand all these compounds were screened against 16S RNA A-site. A basic NHgroup with the correct orientation in this region is required tomaintain the affinity, since acetylation (7a), methylation (7b), removal(6b) of the free NH group and unsaturation of the piperidine ring (6c)all diminished the binding affinity. The NH group is critical,presumably because it forms a hydrogen bond with the negatively chargedphosphate in the RNA backbone. The extended piperidine analogs (6g-6t)showed improved affinities, which, while not wishing to be bound by anyparticular theory, are believed to better orient the NH groups tocontact the phosphate backbone.

Example 18

[0273] One-Pot Synthesis of Benzimidazoles and Their Binding Affinitiesfor E. coli 16S A-site

[0274] A series of piperidine substituted benzimidazoles were preparedaccording to the one-pot procedure of Scheme 18:

[0275] A series of benzimidazole-modified analogs were prepared as shownabove. The procedure required the simple heating of a suitable1,2-dianiline (8) with isonipecotic acid (9) in the presence ofpolyphosphoric acid. The free benzimidazoles were then isolated in goodto excellent yields after basic work-up. From a MS-based assay, it wasestablished that 1) An electron donating groups such as, NH₂ and OMereduced the affinities (1, 10a); 2) Certain hydrophobic substitutionssuch as a methyl (10b), bromo (10c) and chloro (10d) are tolerated; 3)Insertion of nitrogen atoms into the aromatic moiety (10i-10k),particularly at the C4 position (10j) reduced activities; and 4)Electron-withdrawing groups enhanced the affinities (10e-10g).

Example 19

[0276] Synthesis of Additional N-1 Substituted Benzimidazoles and TheirBinding Affinities for E. coli 16S A-site

[0277] A further series of N-1 benzimidazole analogs were preparedaccording to Scheme 19 below:

Solid-phase synthesis of N1 substituted benzimidazoles and their bindingaffinities for E. coli 16S A-site

[0278] This series of compounds were efficiently synthesized byemploying the solid-phase chemistry shown in Scheme 19. Wang resin wasfirst converted into imidazole carbonyl derivative, which was thenallowed to react with compound 10g to give common intermediate 32.Compound 11 reacted readily with a variety of alkylating or acylatingreagents to give the corresponding alkyl or acyl products, which afterremoval of Boc group with 50% TFA in dichloromethane led to the desiredN-1 substituted analogs in excellent yields and purity.

Example 20

[0279] Synthesis of Additional Benzimidazole Dimers and MIC and theirTranscription/Translation Activity

[0280] This series of assays is known to those of skill in the art, andother assays may be substituted therefore without deviating from thespirit and scope hereof. The DNA template, pBestLuc™ (Promega), is aplasmid containing a reporter gene for firefly luciferase fused to astrong tac promoter and ribosome binding site. Messenger RNA from 1 μgpBestLuc is transcribed and translated in E. coli S30 bacterial extractin the presence or absence of test compound. Compounds are tested in ablack 96 well microtiter plate with an assay volume of 35 μL. Each testwell contains: 5 μL test compound, 13 μL S30 premix (Promega), 4 μL 10×complete amino acid mix (1 mM each), 5 μL E. coli S30 extract and 8 μLof 0.125 μg/μL pBestLuc™. The transcription/translation reaction isincubated for 35 minutes at 37° C. followed by detection of functionalluciferase with the addition of 30 μL LucLite™ (Packard). Light outputis quantitated on a Packard TopCount.

[0281] The assays are carried out in 150 μL volume in duplicate in96-well clear flat-bottom plates. The bacterial suspension from anovernight culture growth in appropriate medium is added to a solution oftest compound in 4% DMSO in water. Final bacterial inoculum isapproximately 10⁵-10⁶ CFU/well. The percent growth of the bacteria intest wells relative to that observed for a well containing no compoundis determined by measuring absorbance at 595 nm (A₅₉₅) after 24 h. TheMIC is determined as a range of single compound where the completeinhibition of growth is observed at the higher concentration and cellsare viable at the lower concentrations. Both ampicillin and tetracyclineare used as antibiotic-positive controls in each screening assay for S.pyogenes, E. coli, S. aureus, E. faecalis, K pneumoniae and P. vulgaris.Ciprofloxacin is used as an antibiotic positive control in eachscreening assay for P. aeruginosa.

[0282] Biological activity of selected compounds according to thepresent invention were assayed according to techniques known in the art.

[0283] A series of 2-aminobenzimidazole dimers were synthesizedaccording to the procedure described in Example 11. A series of 5- and6-substituted-2-aminobenzimidazoles also were synthesized, and all wereevaluated for biological activity. Tables 4-7 report MIC andtranscription/translation activity for the dimer compounds By theoutlined procedure. Tables 8 and 9 report the MASS screening of2-aminobenzimidazoles against the Aglla HCV-IRES target. The reportedselectivity was determined by mass spectral analysis of any associationsand provides information about the relative binding affinities. TABLE 4Transcription/ MIC, S. aureus Translation, IC₅₀ Structure MIC, E. coli(μM) (μM) (μM)

12-25 12-25 >100

25-50  75-100    25

25-50 25-50 >100

>100 >100 6-12

>200 >200 >100

25-50  50-100 >100

>200 >200 >200

>50  >50  >100

[0284] TABLE 5

Transcription/32 MIC, S. aureus Translation, IC₅₀ Structure MIC, E. coli(μM) (μM) (μM) X = N(CH₃)₂ 50-75 25-50    20 X = CH₂ >100 >100 >100 X =O >100 >100 >100

[0285] TABLE 6

Transcription/ MIC, S. aureus Translation, IC₅₀ Structure MIC, E. coli(μM) (μM) (μM) X = N-Me 25-50 75-100    25 X = CH₂ >100 >100 >100 X = O 6-12 >100 >100

[0286] TABLE 7

Transcription/ MIC, S. aureus Translation, IC₅₀ Structure MIC, E. coli(μM) (μM) (μM) X = H >100 >100 >100 X = Cl >100 >100 >100

[0287] TABLE 8 MASS Screening of 6-Substituted-2-aminobenzimidazolesagainst Ag IIa HCV IRES Target

Target Ligand conc. conc. % % R (μM) (μM) Complex Dimer Selectivity H2.5 50 125 35 4.30 H 2.5 7.5 33 3 7.49 CH₃ 2.5 50 136 31 6.55 CH₃ 2.57.5 26 0 8.44 OCH₃ 2.5 50 286 39 10.67 OCH₃ 2.5 7.5 52 4 12.89O(CH₂)₃N(CH₃)₂ 2.5 50 862 72 96.88 O(CH₂)₃N(CH₃)₂ 2.5 7.5 46 0 34.53

[0288] TABLE 9 MASS screening of 5-substituted-2-aminobenzimidazolesagainst Ag IIa HCV IRES Target

Target Ligand conc. % % R conc. (μM) (μM) Complex Dimer Selectivity H2.5 50 125 35 4.30 H 2.5 7.5 33 3 7.49 CH₂NH₂ 2.5 7.5 14.7 0 2.0 CH₂NH₂2.5 50 109 80 2.3

[0289] It is intended that each of the patents, applications, andprinted publications including books mentioned in this patent documentbe hereby incorporated by reference in their entirety.

[0290] As those skilled in the art will appreciate, numerous changes andmodifications may be made to the preferred embodiments of the inventionwithout departing from the spirit of the invention. It is intended thatall such variations fall within the scope of the invention.

What is claimed is:
 1. A compound having the Formula I:

wherein: Q₁ is N or CR₃; Q₂ is N or CR₄; Q₃ is N or CR₂₀; Q₄ is N or S;R₁ is H, alkyl, aryl, arylalkyl, heteroaryl; heteroarylalkyl,heterocycloalkyl, arylsulfonyl, aryloxycarbonyl, alkoxyalkoxyalkyl,alkyl-S—R₇, alkyl-NH—C(═O)—R₈ or —R₉—X—R₁₀—R₁₁)H; wherein each of thealkyl, aryl, arylalkyl heteroaryl, heteroarylalkyl, heterocycloalkyl,arylsulfonyl, aryloxycarbonyl and alkoxyalkoxyalkyl moieties in each ofthe foregoing R₁ groups can be optionally substituted with up to 5groups independently selected from the group consisting of C₁-C₆ alkyl,OH, hydroxyalkyl, —C(═O)—R₅; CN, aryl, alkoxycarbonyl, alkylaryl,arylalkyl, heteroaryl, S-heteroaryl optionally substituted with halogen,heteroarylalkyl optionally substituted with halogen, heterocycloalkyloptionally substituted with amino, NO₂, halogen, monohaloalkyl,dihaloalkyl, trihaloalkyl, perhaloaryl, perhaloalkylaryl, alkyl-NR₁₅R₁₆and NR₁₅R₁₆; or one of said alkyl, aryl, arylalkyl heteroaryl,heteroarylalkyl, heterocycloalkyl, arylsulfonyl, aryloxycarbonyl oralkoxyalkoxyalkyl moieties of one of said R₁ groups can be attached to astructure of Formula I at position R₁ thereof; R₃ and R₄ areindependently each H, halogen, C₁-C₆ alkyl, trihaloalkyl,alkoxycarbonyl, alkoxy, NR₁₅R₁₆, and NO₂, wherein said C₁-C₆ alkyl,alkoxycarbonyl, and alkoxy groups can each be optionally substitutedwith NR₁₅R₁₆; R₅ is H, —NHNHR₆, —NHN═CH—R₆, heteroaryl,heterocycloalkyl, wherein said hereteroaryl group can be optionallysubstituted with an aryl or heteroaryl group, R₆ is aryl, heteroaryl;arylsulfonyl, heteroarylsulfonyl, —C(═S)—NH-aryl, —C(═S)—NH-arycarbonyl,—C(═S)—NH-heteroarylcarbonyl, —C(═S)—NH-alkylene-R₂₁, —C(═O)—NH-aryl,—C(═O)—NH-arylcarbonyl, —C(═O)—NH-heteroarylcarbonyl, or—C(═O)—NH-alkylene-R₂₁ where R₂₁ is carboxy, alkoxycarbonyl, aryl,heteroaryl, heterocycloalkyl, arylaminocarbonyl,cycloalkylaminocarbonyl, or a saturated hydrocarbon fused ring systemoptionally having an aryl ring fused thereto, said ring system beingoptionally substituted with up to three alkyl groups on the alkyl oraryl rings thereof; wherein any of said R₆ groups can be optionallysubstituted with up to 3 groups selected from NR₁₅R₁₆, alkyl, hydroxy,halogen, aryl, alkoxy, trihaloalkoxy, arylalkyloxy, NO₂, —SH, —S-alkyl,heteroarylcarbonyl, heteroaryl, alkylheteroaryl, or a moiety of formula—OC₂CH₂—O— attached to adjacent atoms of said R₆ group; R₇ is heteroarylor heterocycloalkyl; R₈ is aryl; R₉ and R₁₀ are each independentlyalkylene having from 1 to about 20 carbons; X is —N(R₁₂)—, —C(R₁₃)(R₁₄)—or O; R₁₁ is H, heterocycloaryl, or alkoxy, wherein saidheterocycloaryl, or alkoxy group can be optionally substituted with upto four groups independently selected from halogen, amino, trihaloalkyl,alkoxycarbonyl, and CN; R₁₂ is H or C₁-C₆ alkyl; and R₁₃ and R₁₄ areeach independently H or C₁-C₆ alkyl. R₁₅ is H, halogen, C₁₋₁₂ alkyl,methylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, branched and straight chain polyaminoalkyl, ora group of formula CH₂(CHOH)₄CH₂OH, wherein said methylcarbonyl,heterocycloalkyl, arylsulfonyl, heteroarylalkyl, aminoalkyl,arylcarbonyl, and branched and straight chain polyaminoalkyl groups canbe substituted by up to 3 OH groups; R₁₆ is H, halogen, or C₁-C₆ alkyl;or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen, or agroup of Formula I at position R₁ threreof; or R₁₅ and R₁₆ together withthe nitrogen atom to which they are attached can form a group of FormulaI wherein said nitrogen atom is Q₄ thereof; provided that when R₃ and R₄are H, R₁ is not: methyl, —CH₂—C(═O)—O—A where A is acyclopentacycloocten-8-yl etser, 1-(1-methylcyclophetyl)piperidin-4-yl,1-(1-phenylcyclophetyl)piperidin-4-yl, or ethoxyethyl.
 2. The compoundof claim 1 wherein Q₁ is CR₃, Q₂ is CR₄, Q₃ is CR₂₀, and Q₄ is N.
 3. Thecompound of claim 2 wherein R₃ and R₄ are each independently halogen,amino, NO₂, CN, C₁₋₆ alkoxy or C₁₋₆ alkyl optionally substituted with upto 3 halogen atoms.
 4. The compound of claim 2 wherein R₃ and R₄ areeach independently halogen, amino, or NO₂.
 5. The compound of claim 2wherein R₃ and R₄ are each independently halogen.
 6. The compound ofclaim 2 wherein R₃ and R₄ are each chlorine.
 7. The compound of claim 2wherein R₁ is alkyl, alkyl substituted with alkoxycarbonyl, alkylsubstituted with carboxy, or aralkyl where said aryl portion of saidaralkyl is phenyl, pyridinyl, or pyrimidinyl, and where said phenyl,pyridinyl, or pyrimidinyl portion of said arylalkyl group is optionallysubstituted with up to 5 substituents selected from halogen,monohaloalkyl, dihaloalkyl, trihaloalkyl, NO₂, alkoxycarbonyl, andalkyl.
 8. The compound of claim 6 wherein R₁ is alkyl, alkyl substitutedwith alkoxycarbonyl, alkyl substituted with carboxy, or aralkyl wheresaid aryl portion of said aralkyl is phenyl, pyridinyl, or pyrimidinyl,and where said phenyl, pyridinyl, or pyrimidinyl portion of saidarylalkyl group is optionally substituted with up to 5 substituentsselected from halogen, monohaloalkyl, dihaloalkyl, trihaloalkyl, NO₂,alkoxycarbonyl, and alkyl.
 9. The compound of claim 7 wherein saidphenyl, pyridinyl, or pyrimidinyl portion of said arylalkyl group isoptionally substituted with up to 5 substituents selected from CF₃, F,Cl, NO₂, COOCH₃, I, Br, and t-butyl.
 10. The compound of claim 8 whereinsaid phenyl, pyridinyl, or pyrimidinyl portion of said arylalkyl groupis optionally substituted with up to 5 substituents selected from CF₃,F, Cl, NO₂, COOCH₃, I, Br, and t-butyl.
 11. The compound of claim 2wherein said R₁ is selected from the radicals shown in Scheme 19, supra.12. The compound of claim 2 wherein R₁ is alkyl substituted with—C(═O)—R₅.
 13. The compound of claim 12 wherein R₅ is —NHNHR₆, or—NHN═CH—R₆.
 14. The compound of claim 13 wherein R₅ is —NHNHR₆.
 15. Thecompound of claim 13 wherein R₅ is —NHN═CH—R₆.
 16. The compound of claim14 wherein R₆ is —C(═O)—NH-aryl, —C(═O)—NH-cycloalkyl, —C(═S)—NH-aryl,arylsulfonyl, heteroarylsulfonyl, heterocycloalkyl, arylaminocarbonyl,cycloalkylaminocarbonyl, —C(═S)—NH-alkylene-R₂₁ where R₂₁ is heteroarylor heterocycloaryl, or a saturated hydrocarbon fused ring systemoptionally having an aryl ring fused thereto, said ring system beingoptionally substituted with up to three alkyl groups on the alkyl oraryl rings thereof; wherein any of said R₆ groups can be optionallysubstituted with up to 3 groups selected from NR₁₅R₁₆, NO₂, a moiety offormula —OC₂CH₂—O— attached to adjacent atoms of said R₆ group, aryl,C₁₋₆ alkoxy, carboxy, or C₁₋₆ trihaloalkoxy.
 17. The compound of claim15 wherein R₆ is aryl or heteroaryl optionally substituted with up to 3groups selected from OH, C₁₋₆ alkoxy, NO₂, C₁₋₆ trihaloalkoxy, C₁₋₆trihaloalkyl, aryl, arylalkyloxy, and a moiety of formula —OC₂CH₂—O—attached to adjacent atoms of said R₆ group.
 18. The compound of claim14 wherein said R₆ is any of the radicals shown in Scheme 16, supra. 19.The compound of claim 15 wherein said R₆ is any of the radicals shown inScheme 15, supra.
 20. The compound of claim 6 wherein R₁ has the formula—(CH₂)_(q)—L₄ where q is 0 to 6 and L₄ is aryl, heteroaryl orheterocycloalkyl, arylsulfonamino, arylcarboxyamino or —S-heteroaryl,where each of said L₄ is optionally substituted with up to threesubstituents selected from halogen and NO₂.
 21. The compound of claim 20wherein said L₄ is N-maleimidyl, N-succinimidyl, N-phthalimidyl,N-naphthalimidyl, N-pyromellitic diimidyl, phenylsulfonamidyl,phenylcarboxamidyl, N-benzopyrrolidinyl, benzimidazol-1-yl,benzimidazol-2-yl, 1,2,4-triazolyl-4-yl, or purinyl, each of said L₄groups being optionally substituted with 1 or 2 substituents selectedfrom halogen, trihaloalkyl, trihaloalkoxy and NO₂.
 22. The compound ofclaim 1 having the formula:

wherein: R₃ and R₄ are independently each H, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, or NO₂; R₃₀ isC₁₋₆ alkyl, heteroarylalkyl, arylalkyl, or heteroaryl, wherein each ofsaid heteroarylalkyl, arylalkyl, or heteroaryl groups each can beoptionally substituted with up to three substitutents selected fromhaloegn, NO₂, and mono-, di-, or trihaloalkyl; or R₃₀ has the structureXX:

wherein R₃₁ is alkylamino, aminoalkylamino, poly(aminoalkyl)amino,heterocycloalkylamino, heterocycloalkyl, —NH—(CHOH)₄—CH₂OH,—NH—(CH₂)₁₋₁₂-heteroaryl or —NH—(CH₂)₁₋₁₂-heterocycloalkyl.
 23. Thecompound of claim 22 wherein R₃₀ has the structure XX.
 24. The compoundof claim 23 wherein R₃₁ is heterocycloalkylamino.
 25. The compound ofclaim 23 wherein R₃₁ is alkylamino.
 26. The compound of claim 23 whereinR₃₁ is aminoalkylamino.
 27. The compound of claim 23 wherein R₃₁ ispoly(aminoalkyl)amino.
 28. The compound of claim 23 wherein R₃₁ isheterocycloalkylamino.
 29. The compound of claim 23 wherein R₃₁ isheterocycloalkyl.
 30. The compound of claim 23 wherein R₃₁ is—NH—(CH₂)₁₋₁₂-heteroaryl.
 31. The compound of claim 23 wherein R₃₁ is—NH—(CH₂)₁₋₁₂-heterocycloalkyl.
 32. The compound of claim 22 wherein R₃₁is any of the radicals shown in Example 11, supra.
 33. The compound ofclaim 22 wherein R₁ is pyridin-4-yl-methyl, pyridin-3yl-methyl,4-fluorophen-1-yl-methyl, 4-nitrophen-1-yl-methyl,4-(bromomethyl)phen-1-yl-methyl, pyrimidine-2-yl, or2,4-dinitrophen-1-yl.
 34. A compound having the structure:

wherein: R₂ is NH₂ or piperidin-4-yl; R₅₀ and R₅, are each independentlyselected from H, halogen, C₁-C₆ alkyl, trihaloalkyl, alkoxycarbonyl,alkoxy, NR₁₅R₁₆, and NO₂, wherein said C₁-C₆ alkyl, alkoxycarbonyl, andalkoxy groups can each be optionally substituted with NR₁₅R₁₆; R₁₅ is H,halogen, C₁₋₁₂ alkyl, methylcarbonyl, heterocycloalkyl, arylsulfonyl,heteroarylalkyl, aminoalkyl, arylcarbonyl, branched and straight chainpolyaminoalkyl, or a group of formula CH₂(CHOH)₄CH₂OH, wherein saidmethylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, and branched and straight chain polyaminoalkylgroups can be substituted by up to 3 OH groups; R₁₆ is H, halogen, orC₁-C₆ alkyl; or R₁₅ and R₁₆ together with the nitrogen atom to whichthey are attached can form a succinimicdo or phthalimido group or afused ring derivative thereof, wherein said succinimido or phthalimidogroup or fused ring derivative thereof can be optionally substituted byup to three substituents independently selected from NO₂ and halogen;R₆₀ is alkylene having from 1 to 18 carbons, or —R₉—X—R₁₀—)H; R₉ and R₁₀are each independently alkylene having from 1 to about 20 carbons; X is—N(R₁₂)—, —C(R₁₃)(R₁₄)— or O; and R₁₂, R₁₃ and R₁₄ are eachindependently H or C₁-C₆ alkyl.
 35. The compound of claim 34 wherein R₂is piperidin-4-yl.
 36. The compound of claim 35 wherein R₅₀ and R₅₁ areeach halogen.
 37. The compound of claim 35 wherein R₅₀ and R₅₁ are eachchlorine.
 38. The compound of claim 37 wherein R₆₀ is alkylene havingfrom 1 to 6 carbons.
 39. The compound of claim 37 wherein R₆₀ isalkylene having from 1 to 4 carbons.
 40. The compound of claim 37wherein R₆₀ is —CH₂—C₆H₄—CH₂—.
 41. The compound of claim 37 wherein R₆₀is para-CH₂—C₆H₄—CH₂—.
 42. The compound of claim 34 wherein R₂ is NH₂.43. The compound of claim 42 wherein R₅₀ and R₅₁ are each independentlyselected from H, halogen, methyl, COOCH₃, CN and CF₃.
 44. The compoundof claim 43 wherein R₆₀ is —R₉—X—R₁₀—.
 45. The compound of claim 44wherein X is —N(R₁₂)—.
 46. The compound of claim 45 wherein R₁₂ ismethyl and R₉ and R₁₀ are each (CH₂)₂ or (CH₂)₃.
 47. The compound ofclaim 46 wherein R₅₀ and R₅₁ are each halogen.
 48. The compound of claim46 wherein R₅₀ and R₅₁ are each H.
 49. The compound of claim 46 whereinR₅₀ is Br and R₅₁ is H.
 50. The compound of claim 46 wherein R₅₀ is CH₃and R₅₁ is H.
 51. The compound of claim 46 wherein R₅₀ is COOCH₃ and R₅₁is H.
 52. The compound of claim 46 wherein R₅₀ is CF₃ and R₅₁ is H. 53.The compound of claim 46 wherein R₅₀ is CN and R₅₁ is H.
 54. Thecompound of claim 44 wherein X is O.
 55. The compound of claim 54wherein R₉ and R₁₀ are each (CH₂)₂ or (CH₂)₃.
 56. The compound of claim55 wherein R₅₀ and R₅₁ are each halogen.
 57. The compound of claim 55wherein R₅₀ and R₅₁ are each H.
 58. The compound of claim 55 wherein R₅₀is Br and R₅₁ is H.
 59. The compound of claim 55 wherein R₅₀ is CH₃ andR₅₁ is H.
 60. The compound of claim 55 wherein R₅₀ is COOCH₃and R₅₁ isH.
 61. The compound of claim 55 wherein R₅₀ is CF₃ and R₅₁ is H.
 62. Thecompound of claim 55 wherein R₅₀ is CN and R₅₁ is H.
 63. A compound offormula:

wherein: R₅₂ and R₅₃ are each independently selected from H, halogen,C₁-C₆ alkyl, trihaloalkyl, alkoxycarbonyl, alkoxy, NR₁₅R₁₆, and NO₂,wherein said C₁-C₆ alkyl, alkoxycarbonyl, and alkoxy groups can each beoptionally substituted with NR₁₅R₁₆; R₁₅ is H, halogen, C₁₋₁₂ alkyl,methylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, branched and straight chain polyaminoalkyl, ora group of formula CH₂(CHOH)₄CH₂OH; wherein said methylcarbonyl,heterocycloalkyl, arylsulfonyl, heteroarylalkyl, aminoalkyl,arylcarbonyl, and branched and straight chain polyaminoalkyl groups canbe substituted by up to 3 OH groups; R₁₆ is H, halogen, or C₁-C₆ alkyl;or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen; and z is1 to
 6. 64. The compound of claim 63 wherein R₁₅ and R₁₆ are eachmethyl.
 65. The compound of claim 64 wherein z is 2 or
 3. 66. Thecompound of claim 65 wherein R₅₂ and R₅₃ are each independently H, C₁₋₆alkyl, alkoxy optionally substituted with dialkylamino, or alkylamino.67. The compound of claim 66 wherein R₅₂ is H.
 68. The compound of claim67 wherein R₅₃ is methyl, methoxy, alkoxy optionally substituted withdialkylamino, or alkylamino.
 69. The compound of claim 67 wherein R₅₃ isOCH₃ or O(CH₂)₃N(CH₃)₂.
 70. The compound of claim 66 wherein R₅₃ is H.71. The compound of claim 70 wherein R₅₂ is methyl, methoxy, alkoxyoptionally substituted with dialkylamino, or alkylamino.
 72. Thecompound of claim 70 wherein R₅₂ is OCH₃ or O(CH₂)₃N(CH₃)₂.
 73. Acompound of Formula:

wherein: R_(2a) is amino, phenyl, mono- or bicyclic heterocycloalkylhaving 1 or 2 ring nitrogen atoms, mono- or bicyclic heteroaryl having 1or 2 ring nitrogen atoms, cycloalkyl, halogen, heterocycloalkylalkyl(i.e., alkyl sub w′ heterocycloalkyl) having 1 or 2 ring nitrogen atoms,mono- or bicyclic heterocycloalkylamino having 1 or 2 ring nitrogenatoms or a group of formula —S-alkylene-L₁ where L₁ is mono- orbicyclic-heteroaryl having 1 or 2 ring nitrogen atoms; wherein each ofsaid amino, phenyl, heterocycloalkyl, heteroaryl, cycloalkyl,heterocycloalkylalkyl, or heterocycloalkylamino groups can be optionallysubstituted with a group selected from amino, OH, C₁-C₁₂ alkyl, astructure of formula —C(═O)CH(NH₂)—L₂ where L₂ is the side chain of anaturally occurring alpha amino acid, —C(NH₂)═NH, C₁-C₁₂ alkylcarbonyl,mono- or bicyclic heteroaryl having 1 or 2 ring nitrogen atoms, mono- orbicyclic heteroarylalkyl having 1 or 2 ring nitrogen atoms, orS-alkyl-heteroaryl where said heteroaryl is mono- or bicyclic having 1or 2 ring nitrogen atoms; and R₃ and R₄ are each independently halogen,amino, NO₂, CN, C₁₋₆ alkoxy or C₁₋₆ alkyl optionally substituted with upto 3 halogen atoms; and R₃₀ is H, alkyl, aryl, arylalkyl, heteroaryl;heteroarylalkyl, heterocycloalkyl, arylsulfonyl, aryloxycarbonyl,alkoxyalkoxyalkyl, alkyl-S—R₇, alkyl-NH—C(═O)—R₈ or —R₉—X—R₁₀—R₁₁)H;wherein each of the alkyl, aryl, arylalkyl heteroaryl, heteroarylalkyl,heterocycloalkyl, arylsulfonyl, aryloxycarbonyl and alkoxyalkoxyalkylmoieties in each of the foregoing R₁ groups can be optionallysubstituted with up to 3 groups independently selected from the groupconsisting of C₁-C₆ alkyl, OH, hydroxyalkyl, —C(═O)—R₅, CN, aryl,alkoxycarbonyl, alkylaryl, arylalkyl, heteroaryl, S-heteroaryloptionally substituted with halogen, heteroarylalkyl optionallysubstituted with halogen, heterocycloalkyl optionaly substituted withamino, NO₂, halogen, monohaloalkyl, dihaloalkyl, trihaloalkyl,perhaloaryl, perhaloalkylaryl, alkyl-NR₁₅R₁₆ and NR₁₅R₁₆; or one of saidalkyl, aryl, arylalkyl heteroaryl, heteroarylalkyl, heterocycloalkyl,arylsulfonyl, aryloxycarbonyl or alkoxyalkoxyalkyl moieties of one ofsaid R₁ groups can be attached to a structure of Formula I at positionR₁ thereof; R₅ is H, —NHNHR₆, —NHN═CH—R₆, heteroaryl, heterocycloalkyl,wherein said hereteroaryl group can be optionally substituted with anaryl or heteroaryl group, R₆ is aryl, heteroaryl; arylsulfonyl,heteroarylsulfonyl, —C(═S)—NH-aryl, —C(═S)—NH-arylcarbonyl,—C(═S)—NH-heteroarylcarbonyl, —C(═S)—NH-alkylene-R₂₁, —C(═O)—NH-aryl,—C(═O)—NH-arylcarbonyl, —C(═O)—NH-heteroarylcarbonyl, or—C(═O)—NH-alkylene-R₂₁ where R₂₁ is carboxy, alkoxycarbonyl, aryl,heteroaryl, heterocycloalkyl, arylaminocarbonyl,cycloalkylaminocarbonyl, or a saturated hydrocarbon fused ring systemoptionally having an aryl ring fused thereto, said ring system beingoptionally substituted with up to three alkyl groups on the alkyl oraryl rings thereof, wherein any of said R₆ groups can be optionallysubstituted with up to 3 groups selected from NR₁₅R₁₆, alkyl, hydroxy,halogen, aryl, alkoxy, trihaloalkoxy, arylalkyloxy, NO₂, —SH, —S-alkyl,heteroarylcarbonyl, heteroaryl, alkylheteroaryl, or a moiety of formula—OC₂CH₂—O— attached to adjacent atoms of said R₆ group; R₇ is heteroarylor heterocycloalkyl; R₈ is aryl; R₉ and R₁₀ are each independentlyalkylene having from 1 to about 20 carbons; X is —N(R₁₂)—, —C(R₁₃)(R₁₄)—or O; R₁₁ is H, heterocycloaryl or alkoxy, wherein said heterocycloarylor alkoxy group can be optionally substituted with up to four groupsindependently selected from halogen, amino, trihaloalkyl,alkoxycarbonyl, and CN; R₁₂ is H or C₁-C₆ alkyl; and R₁₃ and R₁₄ areeach independently H or C₁-C₆ alkyl; R₁₅ is H, halogen, C₁₋₁₂ alkyl,methylcarbonyl, heterocycloalkyl, arylsulfonyl, heteroarylalkyl,aminoalkyl, arylcarbonyl, branched and straight chain polyaminoalkyl, ora group of formula CH₂(CHOH)₄CH₂OH, wherein said methylcarbonyl,heterocycloalkyl, arylsulfonyl, heteroarylalkyl, aminoalkyl,arylcarbonyl, and branched and straight chain polyaminoalkyl groups canbe substituted by up to 3 OH groups; R₁₆ is H, halogen, or C₁-C₆ alkyl;or R₁₅ and R₁₆ together with the nitrogen atom to which they areattached can form a succinimicdo or phthalimido group or a fused ringderivative thereof, wherein said succinimido or phthalimido group orfused ring derivative thereof can be optionally substituted by up tothree substituents independently selected from NO₂ and halogen, or agroup of Formula I at position R₁ threreof; or R₁₅ and R₁₆ together withthe nitrogen atom to which they are attached can form a group of FormulaI wherein said nitrogen atom is Q₄ thereof;
 74. The compound of claim 73wherein R₃ and R₄ are each halogen.
 75. The compound of claim 73 whereinR₃ and R₄ are each chlorine.
 76. The compound of claim 73 wherein R_(2a)is amino, Cl, phenyl, monocyclic heterocycloalkyl having 1 or 2 ringnitrogen atoms, monocyclic heteroaryl having 1 ring nitrogen atom,cyclopenyl, cyclohexyl, heterocycloalkyl-methyl, piperidine-4-yl aminoor a group of formula —S—(C₂₋₄ alkylene)-N-phthalimido; wherein each ofsaid phenyl, heterocycloalkyl heteroaryl, cyclopenyl, cyclohexyl,heterocycloalkyl-methyl, and piperidine-4-yl amino groups can beoptionally substituted with a group selected from NH₂, OH, CH₃, COOCH₃,a structure of formula —(═O)CH(NH₂)—L₂ where L₂ is a serine or threonineside chain, —C(NH₂)═NH, benzimidazolyl, or benzimidazolemethylyl. 77.The compound of claim 75 wherein R_(2a) is amino, Cl, phenyl, monocyclicheterocycloalkyl having 1 or 2 ring nitrogen atoms, monocyclicheteroaryl having 1 ring nitrogen atom, cyclopenyl, cyclohexyl,heterocycloalkyl-methyl, piperidine-4-yl amino or a group of formula—S—(C₂₋₄ alkylene)-N-phthalimido; wherein each of said phenyl,heterocycloalkyl heteroaryl, cyclopenyl, cyclohexyl,heterocycloalkyl-methyl, and piperidine-4-yl amino groups can beoptionally substituted with a group selected from NH₂, OH, CH₃, COOCH₃,a structure of formula —(═O)CH(NH₂)—L₂ where L₂ is a serine or threonineside chain, —C(NH₂)═NH, benzimidazole, or benzimidazolemethyl.
 78. Thecompound of claim 73 wherein R_(2a) is amino, Cl, piperidinyl,pyridinyl, phenyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,—CH₂-piperazinyl, piperidine-4-yl-amino or S-alkyl-phthalyl, whereinsaid piperidinyl, pyridinyl, phenyl, cyclopentyl, cyclohexyl,pyrrolidinyl, piperazinyl, —CH₂-piperazinyl, or S-alkyl-phthalyl groupscan be optionally substituted with a group selected from NH₂,methylcarbonyl, —C(═O)CH(NH₂)—CH₂OH, methyl, OH, —C(NH₂)═NH, OH,benzimidazole-2-yl, and —CH₂-benzimidazole-2-yl.
 79. The compound ofclaim 75 wherein R_(2a) is amino, Cl, piperidinyl, pyridinyl, phenyl,cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, —CH₂-piperazinyl,piperidine-4-yl-amino or S-alkyl-phthalyl, wherein said piperidinyl,pyridinyl, phenyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl,—CH₂-piperazinyl, or S-alkyl-phthalyl groups can be optionallysubstituted with a group selected from NH₂, methylcarbonyl,—C(═O)CH(NH₂)—CH₂OH, methyl, OH, —C(NH₂)═NH, OH, benzimidazole-2-yl, and—CH₂-benzimidazole-2-yl.
 80. The compound of claim 73 wherein R_(2a) isamino, Cl, pyridin-4-yl, phenyl substituted with amino, cyclopentylsubstituted with amino, cyclohexyl optionally substituted with amino,pyrrolidin-2-yl optionally substituted by hydroxy, piperazin-1-yloptionally substituted at the 4-yl position by benzimidazole-2-yl,piperazin-1-yl-methyl optionally substituted at the 4-yl position by—CH₂-benzimidazole-2-yl, piperidine-4-yl-amino, piperidin-1-ylsubstituted by amino, S-alkyl-phthalyl, or said R₂ is piperidin-4-yloptionally substituted at the 1-yl position with —C(═O)CH₃,—C(═O)CH(NH₂)—CH₂OH, —C(NH₂)═NH, or CH₃.
 81. The compound of claim 75wherein R_(2a) is amino, Cl, pyridin-4-yl, phenyl substituted withamino, cyclopentyl substituted with amino, cyclohexyl optionallysubstituted with amino, pyrrolidin-2-yl optionally substituted byhydroxy, piperazin-1-yl optionally substituted at the 4-yl position bybenzimidazole-2-yl, piperazin-1-yl-methyl optionally substituted at the4-yl position by —CH₂-benzimidazole-2-yl, piperidine-4-yl-amino,piperidin-1-yl substituted by amino, S-alkyl-phthalyl, or said R₂ ispiperidin-4-yl optionally substituted at the 1-yl position with—C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH, —C(NH₂)═NH, or CH₃.
 82. The compound ofclaim 73 wherein R_(2a) is amino, piperidin-4-yl-amino, piperiazine-1-yloptionally substituted with benzimidazole-2-yl, pyridin-4-yl,piperidin-4-yl optionally substituted at the 1-yl position with—C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH, —C(NH₂)═NH, or CH₃,4-amino-piperdin-1-yl, 3-amino-phen-1-yl, 3-amino-cyclopent-1-yl,cyclohexyl optionally substituted at the 3-yl or 4-yl position with NH₂,4-hydroxypyrrolidin-2-yl, piperazin-1-yl-methyl,4-(benzimidazole-2-yl-methyl)piperazin1-yl-methyl, or S-alkyl-phthalylwhere said alkyl has from 2 to 4 carbons.
 83. The compound of claim 73wherein R_(2a) is piperidin-4-yl optionally substituted at the 1-ylposition with —C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH, —C(NH₂)═NH, or CH₃. 84.The compound of claim 75 wherein R_(2a) is piperidin-4-yl optionallysubstituted at the 1-yl position with —C(═O)CH₃, —C(═O)CH(NH₂)—CH₂OH,—C(NH₂)═NH, or CH₃.
 85. The compound of claim 73 wherein R_(2a) ispiperidin-4-yl.
 86. The compound of claim 75 wherein R_(2a) ispiperidin-4-yl.
 87. The compound of claim 73 wherein R_(2a) is NH₂. 88.The compound of claim 75 wherein R_(2a) is NH₂.
 89. The compound ofclaim 86 wherein R₃₀ is alkyl substituted with —C(═O)—R₅.
 90. Thecompound of claim 89 wherein R₅ is —NHNHR₆, or —NHN═CH—R₆.
 91. Thecompound of claim 90 wherein R₅ is —NHNHR₆.
 92. The compound of claim 90wherein R₅ is —NHN═CH—R₆.
 93. The compound of claim 91 wherein R₆ is—C(═O)—NH-aryl, —C(═O)—NH-cycloalkyl, —C(═S)—NH-aryl, arylsulfonyl,heteroarylsulfonyl, heterocycloalkyl, arylaminocarbonyl,cycloalkylaminocarbonyl, —C(═S)—NH-alkylene-R₂₁ where R₂₁ is heteroarylor heterocycloaryl, or a saturated hydrocarbon fused ring systemoptionally having an aryl ring fused thereto, said ring system beingoptionally substituted with up to three alkyl groups on the alkyl oraryl rings thereof, wherein any of said R₆ groups can be optionallysubstituted with up to 3 groups selected from NR₁₅R₁₆, NO₂, a moiety offormula —OC₂CH₂—O— attached to adjacent atoms of said R₆ group, aryl,C₁₋₆ alkoxy, carboxy, or C₁₋₆ trihaloalkoxy.
 94. The compound of claim92 wherein R₆ is aryl or heteroaryl optionally substituted with up to 3groups selected from OH, C₁₋₆ alkoxy, NO₂, C₁₋₆ trihaloalkoxy, C₁₋₆trihaloalkyl, aryl, arylalkyloxy, and a moiety of formula —OC₂CH₂—O—attached to adjacent atoms of said R₆ group.
 95. A compound as describedin Table, supra.
 96. The compound of claim 86 wherein R₃₀ has theformula —(CH₂)_(q)—L₄ where q is 0 to 6 and L₄ is aryl, heteroaryl orheterocycloalkyl, arylsulfonamino, arylcarboxyamino or —S-heteroaryl,where each of said L₄ is optionally substituted with up to threesubstituents selected from halogen and NO₂.
 97. The compound of claim 96wherein said L₄ is maleimido, succinimido, phthalimido, naphthalimido,pyromellitic diimido, phenylsulfonamido, phenylcarboxamido,benzopyrrolidine, benzimidazole, triazole, or —S-benzimidazole.
 98. Acompound of Formula:

wherein: Q₅ is CH or N; Q₆is C—R₆₁ or N; Q₇is C—R₆₀ or N; R₆₀ and R₆₁are each independently H, halogen, C₁₋₆ alkyl, trihaloalkyl, or C₁₋₆alkoxy; provided that when Q₆ is C—R₆₁, Q₇ is C—R₆₀ and Q₅is CH, thenR₆₀ and R₆₁ are not both H.
 99. The compound of claim 98 wherein Q₅ isN.
 100. The compound of claim 98 wherein Q₆ is N.
 101. The compound ofclaim 98 wherein Q₇ is N.
 101. The compound of claim 98 wherein Q₅ is N,Q₆is C—R₆₁ and Q₇is C—R₆₀.
 102. The compound of claim 98 wherein Q₇ isN, Q₆is C—R₆₁ and Q₅is CH.
 103. The compound of claim 98 wherein Q₅ isN, Q₆is N and Q₇ is C—R₆₀.
 104. The compound of claim 98 wherein Q₅ isCH, Q₆is R₆₁ and Q₇is C—R₆₀.
 105. The compound of claim 104 wherein R₆₀and R₆₁ are each independently H, Br, Cl, methoxy, methyl ortrifluoromethyl.
 106. The compound of claim 104 wherein R₆₀ is OCH₃ andR₆₁ is H, or R₆₀ is CH₃ and R₆₁ is H, or R₆₀is Br and R₆₁ is H, or R₆₀is Cl and R₆₁ is H, or R₆₀ r is CF₃and R₆₁ is H, or R₆₀ is Cl and R₆₁ isCH₃, or R₆₀ and R₆₁ are both Cl.